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Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion
Open accessAbstract
Hereditary spastic paraplegia–associated mutations in a WASH complex component impair integrin-mediated cell adhesion.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
Strumpellin/WASHC5 interacts with CAV1 and helps maintain CAV1 and α5 integrin levels by limiting their lysosomal degradation, thereby supporting integrin-mediated cell adhesion. SPG8-associated strumpellin missense mutants fail to rescue endosomal tubulation, CAV1 abundance, integrin localization, and fibronectin-mediated spreading defects.
Key findings
- Strumpellin co-purified with CAV1 and other WASH complex components; depletion of strumpellin or WASH1 reduced total CAV1 protein and CAV1-positive intracellular vesicles, with total CAV1 fluorescence reduced to about half of control, while CAV1 transcripts were unaffected.
- Bafilomycin A1 restored CAV1 abundance in strumpellin-depleted cells, indicating enhanced lysosomal degradation; α5 integrin also accumulated intracellularly, colocalized with LAMP1, and was reduced in total protein, with Baf A1 restoring its abundance.
- Four SPG8 missense mutants in the spectrin-repeat domain (N471D, L619F, V626F, G696A), expressed at ~30% of endogenous strumpellin, failed to rescue endosomal tubulation, CAV1 abundance/vesicles, α5 integrin localization to focal adhesions, or cell spreading on 20 μg/ml fibronectin, whereas wild-type strumpellin rescued these phenotypes.
- The CAV1-binding region was mapped to strumpellin residues 608–790; a CAV1-binding-deficient strumpellin mutant failed to rescue α5 integrin abundance, and endosomally targeted WASH1-VCA actin nucleation activity restored CAV1 abundance and vesicle localization in WASH complex–depleted cells.
Methods
- Tandem affinity purification and mass spectrometry in hTERT-RPE1 cells stably expressing strumpellin-ZTF, plus co-immunoprecipitation, immunoblotting, and quantitative real-time PCR.
- siRNA/shRNA depletion of strumpellin or WASH1 in hTERT-RPE1 cells and rat cerebral cortical neurons, with stable expression of wild-type or SPG8 mutant strumpellin and a FAM21Δ356-WASH1-VCA fusion; assays included immunofluorescence confocal microscopy, cycloheximide and bafilomycin A1 treatments, CT-B uptake, and fibronectin cell-spreading assays.
- Statistical testing used Shapiro-Wilk normality testing, Wilcoxon rank-sum tests for two groups, and Kruskal-Wallis with Dunnett’s post hoc test for multiple groups; P < 0.05 was considered significant.
Limitations
- The paper states that future work is needed to correlate the various roles of different WASHC5 mutation types with different phenotypic presentations, and notes that the range of disease phenotypes due to different WASHC5 mutations may be more complex.
- Evident from the text, not explicitly framed as a limitation: most mechanistic experiments use siRNA/shRNA depletion plus stable expression of mutant strumpellin rather than patient-derived cells or knock-in of mutations at the endogenous locus.
- Evident from the text, not explicitly framed as a limitation: the SPG8 mutant proteins were expressed at ~30% of endogenous strumpellin, and no in vivo SPG8 animal model or rescue of axonopathy is reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
7 of 28 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Findingown data
Maintenance of CAV1 protein levels depends on the WASH complex.
“Thus, maintenance of CAV1 protein levels depended on the WASH complex.”
Quote in the paperSubstantial claim - Findingown data
Strumpellin interacts with CAV1.
“Caveolin-1 (CAV1), a key component of caveolae, interacted with strumpellin in cells, and strumpellin inhibited lysosomal degradation of CAV1.”
- Also stated in: § Strumpellin interacts with CAV1 · plain
“Additionally, we identified CAV1, a major membrane protein component of caveolae – flask-shaped, lipid-rich pits enriched in the plasma membrane but also present in some intracellular membranes – as a previously unknown strumpellin-interacting protein (Fig. 1A and table S1).”
Quote in the paperSubstantial claim - Also stated in: § Strumpellin interacts with CAV1 · plain
- Findingown data
Trafficking of CT-B is not affected by strumpellin depletion.
“On the other hand, trafficking of CT-B, another cargo of caveolae, was not affected by strumpellin depletion (Fig. 5D).”
Quote in the paperSubstantial claim - Findingown data
Intracellular α5 integrin mainly colocalizes with lysosomal marker LAMP1 in strumpellin-depleted cells.
“Intracellular α5 integrin mainly colocalized with the lysosomal marker LAMP1 in strumpellin-depleted cells (Fig. 5B), suggesting that loss of strumpellin facilitated lysosomal degradation of α5 integrin.”
Quote in the paperSubstantial claim - Findingown data
SPG8-associated missense mutations in strumpellin do not rescue the reduction of CAV1 protein in strumpellin-deficient cells.
“SPG8-associated missense mutations in strumpellin did not rescue endosomal tubulation defects, reduction of CAV1 protein, or integrin-mediated cell adhesion in strumpellin-deficient cells.”
- Also stated in: § SPG8 mutant strumpellin proteins are defective in endosomal fission and maintenance of CAV1 · boosted
“Strikingly, all tested SPG8 missense mutants failed to rescue the reduction of CAV1 abundance caused by strumpellin depletion (Fig. 4B).”
Quote in the paperSubstantial claim - Also stated in: § SPG8 mutant strumpellin proteins are defective in endosomal fission and maintenance of CAV1 · boosted
- Findingown data
The stably expressed FAM21Δ356-WASH1-VCA fusion protein reverses the reduction of CAV1 abundance caused by depletion of WASH1 or strumpellin.
“The stably-expressed, FLAG-tagged FAM21Δ356-WASH1-VCA fusion protein reversed the reduction of CAV1 abundance caused by depletion of WASH1 or strumpellin (Fig. 7A).”
Quote in the paperSubstantial claim - Findingown data
The decrease in CAV1 protein upon WASH complex depletion is not due to transcriptional changes.
“This decrease in CAV1 protein was not due to transcriptional changes, because CAV1 transcripts were unaffected by the depletion of WASH complex components (fig. S1).”
Quote in the paperSubstantial claim - Findingown data
Depletion of strumpellin in cultured rat cerebral cortical neurons reduces CAV1 abundance.
“In cultured rat cerebral cortical neurons depleted of strumpellin using short hairpin RNAs (shRNAs), a similar reduction in CAV1 abundance occurred, suggesting that this reduction may be relevant for SPG8 pathogenesis (Fig. 2, E and F).”
Quote in the paperSubstantial claim - Findingown data
α5 integrin distribution to focal adhesions is rescued by wild-type strumpellin but not by SPG8-associated strumpellin mutants.
“Furthermore, α5 integrin distribution to focal adhesions was rescued upon expression of wild-type strumpellin, but not by the the expression of SPG8-associated strumpellin mutants (Fig. 5A), suggesting that caveolar-mediated trafficking of α5 integrin may be linked to SPG8 pathogenesis.”
Quote in the paperSubstantial claim - Findingown data
Total protein amounts of α5 integrin are reduced in strumpellin-depleted cells.
“Indeed, total protein amounts of α5 integrin were reduced in strumpellin-depleted cells (Fig. 5C).”
Quote in the paperSubstantial claim - Findingown data
SPG8-associated mutant strumpellin proteins are defective in CAV1-dependent, integrin-mediated cell adhesion.
“Together, these results demonstrate that SPG8-associated mutant strumpellin proteins were defective in CAV1-dependent, integrin-mediated cell adhesion, suggesting that SPG8 could be associated with abnormalities in CAV1-dependent, integrin-mediated cell adhesion.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Findingown data
Ectopically expressed HA-tagged CAV1 interacts only with strumpellin and SWIP among WASH complex components.
“Ectopically-expressed, HA-tagged CAV1 interacted only with strumpellin and SWIP (Fig. 1D).”
Quote in the paperNot a substantial claim - Findingown data
SPG8-associated missense mutations in strumpellin do not rescue endosomal tubulation defects in strumpellin-deficient cells.
“SPG8-associated missense mutations in strumpellin did not rescue endosomal tubulation defects, reduction of CAV1 protein, or integrin-mediated cell adhesion in strumpellin-deficient cells.”
- Also stated in: § SPG8 mutant strumpellin proteins are defective in endosomal fission and maintenance of CAV1 · plain
“However, none of the SPG8 mutants tested rescued the endosomal tubulation phenotype, whereas all tested SPG8 mutants rescued the aberrant formation of collapsed endosomes.”
- Also stated in: § Discussion · plain
“Expression of four different SPG8 missense mutant strumpellin proteins showed a similar endosomal tubulation defect (Fig. 4D), which is known to induce aberrant endosomal recycling.”
Quote in the paperSubstantial claim - Also stated in: § SPG8 mutant strumpellin proteins are defective in endosomal fission and maintenance of CAV1 · plain
- Findingown data
CAV1 interacts with the WASH complex.
“The interaction of CAV1 with the WASH complex was confirmed by co-immunoprecipitation (Fig. 1, C and D).”
Quote in the paperSubstantial claim - Findingown data
SPG8-associated missense mutations in strumpellin do not rescue integrin-mediated cell adhesion in strumpellin-deficient cells.
“SPG8-associated missense mutations in strumpellin did not rescue endosomal tubulation defects, reduction of CAV1 protein, or integrin-mediated cell adhesion in strumpellin-deficient cells.”
- Also stated in: § SPG8-associated mutations impair integrin-mediated cell adhesion · plain
“This spreading defect was not rescued by expression of SPG8-associated strumpellin mutants, but it was rescued by wild-type strumpellin (Fig. 5, E and F).”
Quote in the paperSubstantial claim - Also stated in: § SPG8-associated mutations impair integrin-mediated cell adhesion · plain
- Findingown data
Strumpellin-depleted cells spread less on fibronectin (20 μg/ml) than control cells.
“Strumpellin-depleted cells spread less on an intermediate concentration of fibronectin (20 μg/ml) than did control cells (Fig. 5, E and F), similar to findings in WASH1-depleted cells (16).”
Quote in the paperSubstantial claim - Findingown data
Residues 608-790 of strumpellin are critical for binding to CAV1 in cells.
“We identified the central spectrin-repeat domain of strumpellin (residues 241-790) as a major CAV1-binding region (Fig. 6A), with residues 608-790 being critical for binding to CAV1 in cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
The FAM21Δ356-WASH1-VCA fusion protein rescues CAV1 localization at intracellular vesicles.
“The FAM21Δ356-WASH1-VCA fusion protein also rescued CAV1 localization at intracellular vesicles (Fig. 7, B and C).”
Quote in the paperSubstantial claim - Findingown data
Treatment with Baf A1 restores α5 integrin abundance in strumpellin-depleted cells to approximately control levels.
“As expected, treatment with Baf A1 restored α5 integrin abundance in strumpellin-depleted cells to approximately those in control cells, further indicating that depletion of strumpellin facilitated lysosomal degradation of α5 integrin.”
Quote in the paperSubstantial claim - Findingown data
All tested SPG8 mutants rescue aberrant formation of collapsed endosomes.
“However, none of the SPG8 mutants tested rescued the endosomal tubulation phenotype, whereas all tested SPG8 mutants rescued the aberrant formation of collapsed endosomes.”
Quote in the paperSubstantial claim - Findingown data
The central spectrin-repeat domain of strumpellin (residues 241-790) is a major CAV1-binding region.
“We identified the central spectrin-repeat domain of strumpellin (residues 241-790) as a major CAV1-binding region (Fig. 6A), with residues 608-790 being critical for binding to CAV1 in cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
Wild-type strumpellin rescues endosomal tubulation phenotype and aggregation of WASH complex at collapsed endosomes induced by depletion of endogenous strumpellin.
“Stably-expressed wild-type strumpellin proteins rescued both an endosomal tubulation phenotype and aggregation of the WASH complex at collapsed endosomes, which are induced by the depletion of endogenous strumpellin (Fig. 4, D and E, and fig. S2).”
Quote in the paperSubstantial claim - Premisecitation
Mutations in WASHC5 cause autosomal dominant hereditary spastic paraplegia type SPG8.
“Mutations in WASHC5 (also known as KIAA0196) cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG8.”
- Also stated in: § Introduction · plain
“Autosomal dominant mutations in the WASHC5 (also known as KIAA1096) gene, which encodes a protein known as strumpellin or WASHC5, cause an often severe, mostly pure HSP termed SPG8 (MIM #603563) (6), though ataxia and axonal sensory neuropathy have also been observed in SPG8 patients (7, 8).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Valdmanis PN, Meijer IA, Reynolds A, Lei A, MacLeod P, Schlesinger D, Zatz M, Reid E, Dion PA, Drapeau P, Rouleau GA, Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am. J. Hum. Genet 80, 152– 161 (2007). 17160902 PMC1785307 source
- Also stated in: § Introduction · plain
- Premisecitation
Strumpellin is a core component of the WASH complex that activates Arp2/3-mediated actin polymerization on endosomes.
“WASHC5, commonly called strumpellin, is a core component of the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex that activates actin nucleation at endosomes.”
- Also stated in: § Introduction · plain
“Strumpellin is a core component of the hetero-pentameric Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex that activates Arp2- and Arp3-mediated actin polymerization on endosomes (9, 10).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Jia D, Gomez TS, Metlagel Z, Umetani J, Otwinowski Z, Rosen MK, Billadeau DD, WASH and WAVE actin regulators of the Wiskott-Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes. Proc. Natl. Acad. Sci. U. S. A 107, 10442– 10447 (2010). 20498093 PMC2890800 source
- cites [10] Rotty JD, Wu C, Bear JE, New insights into the regulation and cellular functions of the ARP2/3 complex. Nat. Rev. Mol. Cell Biol 14, 7– 12 (2013). 23212475 source
- Also stated in: § Introduction · plain
- Interpretationown data
Strumpellin depletion enhances lysosomal degradation of CAV1.
“Treatment of cells with bafilomycin (Baf) A1, which inhibits protein degradation at lysosomes, restored CAV1 abundance in strumpellin-depleted cells, similarly to its effects on control cells (Fig. 3B), indicating that strumpellin depletion enhanced lysosomal degradation of CAV1.”
Quote in the paperSubstantial claim - Interpretationown data
Strumpellin selectively affects specific types of caveolar-mediated trafficking.
“These results demonstrate that strumpellin selectively affected specific types of caveolar-mediated trafficking.”
Quote in the paperSubstantial claim - Interpretationown data
Strumpellin inhibits lysosomal degradation of CAV1.
“Caveolin-1 (CAV1), a key component of caveolae, interacted with strumpellin in cells, and strumpellin inhibited lysosomal degradation of CAV1.”
- Also stated in: § Discussion · hedged
“Our results further indicate that strumpellin fine-tunes CAV1 protein levels by inhibiting its lysosomal degradation (Fig. 8), perhaps akin to its role in low-density lipoprotein receptor sorting and lysosomal degradation (18).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationreasoning
SPG8 etiology is closely linked to CAV1-dependent, integrin-mediated cell adhesion.
“The fact that the regions in which pathogenic SPG8 mutations are concentrated are required for CAV1 binding strongly supports the notion that SPG8 etiology is closely linked to CAV1-dependent, integrin-mediated cell adhesion.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Rests on an assumption: Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
- Interpretationreasoning
The differential regulatory mechanism of strumpellin appears to originate from its role in endosomal recycling.
“This differential regulatory mechanism of strumpellin appears to originate from its role in endosomal recycling.”
Quote in the paperSubstantial claim - Interpretationown data
Depletion of strumpellin facilitates lysosomal degradation of α5 integrin.
“Intracellular α5 integrin mainly colocalized with the lysosomal marker LAMP1 in strumpellin-depleted cells (Fig. 5B), suggesting that loss of strumpellin facilitated lysosomal degradation of α5 integrin.”
- Also stated in: § SPG8-associated mutations impair integrin-mediated cell adhesion · hedged
“As expected, treatment with Baf A1 restored α5 integrin abundance in strumpellin-depleted cells to approximately those in control cells, further indicating that depletion of strumpellin facilitated lysosomal degradation of α5 integrin.”
Quote in the paperSubstantial claim - Also stated in: § SPG8-associated mutations impair integrin-mediated cell adhesion · hedged
- Interpretationown data
CAV1 and WASH components interact at endosomes.
“Fluorescence signals for WASH complex components strumpellin, FAM21, and CCDC53, all of which are known to localize to endosomes, partially overlapped with CAV1-immunoreactive signals on intracellular vesicles (Fig. 1F), suggesting that CAV1 and WASH components interacted at endosomes.”
Quote in the paperSubstantial claim - Interpretationown data
The actin nucleation activity of WASH1 is required for maintenance of CAV1 at intracellular membranes.
“These results indicate that the actin nucleation activity of WASH1 was required for maintenance of CAV1 at intracellular membranes.”
Quote in the paperSubstantial claim - Interpretationown data
Strumpellin fine-tunes CAV1 protein levels by inhibiting its lysosomal degradation.
“Our results further indicate that strumpellin fine-tunes CAV1 protein levels by inhibiting its lysosomal degradation (Fig. 8), perhaps akin to its role in low-density lipoprotein receptor sorting and lysosomal degradation (18).”
Quote in the paperSubstantial claim - Interpretationown data
The interaction of strumpellin with CAV1 stimulates integrin recycling, thereby promoting cell adhesion.
“In addition, the interaction of strumpellin with CAV1 stimulated integrin recycling, thereby promoting cell adhesion.”
Quote in the paperSubstantial claim - Interpretationown data
The WASH complex can positively regulate integrin-mediated cell adhesion through CAV1.
“Previous studies have identified disturbances of integrin trafficking and cell adhesion in WASH-depleted cells (13, 16), and we now demonstrate that the WASH complex can positively regulate integrin-mediated cell adhesion through CAV1.”
Quote in the paperSubstantial claim - Interpretationown data
The interaction of strumpellin with CAV1 mediates the recycling of α5 integrin.
“These results indicate that the interaction of strumpellin with CAV1 mediates the recycling of α5 integrin.”
Quote in the paperSubstantial claim - Premisecitation
CAV1 enhances pro-survival and pro-growth signaling by concentrating neurotransmitter and neurotrophin receptors at membrane microdomains and/or lipid rafts, modulating pathways such as cAMP formation.
“For instance, CAV1 enhances pro-survival and pro-growth signaling by concentrating neurotransmitter and neurotrophin receptors at membrane microdomains and/or lipid rafts, thus modulating signaling pathways such as the formation of cyclic adenosine monophosphate (cAMP), which has been shown to regulate the growth and guidance of developing axons (46).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Murray AJ, Tucker SJ, Shewan DA, cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J. Neurosci 29, 15434– 15444 (2009). 20007468 PMC6666109 source
- Interpretationown data
The WASH complex maintains CAV1 and integrin protein levels by inhibiting their lysosomal degradation through its endosomal actin nucleation activity.
“Mechanistically, we demonstrated that the WASH complex maintained CAV1 and integrin protein levels by inhibiting their lysosomal degradation through its endosomal actin nucleation activity.”
Quote in the paperSubstantial claim - Interpretationown data
Defects in the CAV1-dependent, integrin-mediated adhesion pathway could account for the pathogenic mechanism of hereditary spastic paraplegia caused by the most compelling SPG8 missense mutations.
“Taken together, our results suggest that defects in the CAV1-dependent, integrin-mediated adhesion pathway could account for the pathogenic mechanism of HSP caused by the most compelling SPG8 missense mutations.”
Quote in the paperSubstantial claim - Premisecitation
Expression of some SPG8 missense mutants does not cause alterations in endosomal tubulation, endosomal recycling, or WASH complex assembly.
“Moreover, expression of some SPG8 missense mutants do not cause alterations in endosomal tubulation, endosomal recycling, or WASH complex assembly, which are known to be induced by strumpellin depletion (26, 38).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [26] Freeman C, Seaman MNJ, Reid E, The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function. Biochim. Biophys. Acta 1832, 160– 173 (2013). 23085491 PMC3714738 source
- cites [38] Clemen CS, Tangavelou K, Struckberg K-H, Just S, Gaertner L, Regus-Leidig H, Stumpf M, Reimann J, Coras R, Morgan RO, Fernandez M-P, Hofmann A, Müller S, Schoser B, Hanisch F-G, Rottbauer W, Blümcke I, von Hörsten S, Eichinger L, Schröder R, Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain 133, 2920– 2941 (2010). 20833645 source
- Interpretationcitation
Because gene products implicated in several other forms of HSP are involved in endosomal tubulation and impact lysosomal function, this pathway could represent an important converging theme in HSP pathogenesis.
“Because the gene products implicated in several other forms of HSP, including the most common SPG4 form, are also involved in endosomal tubulation and impact lysosomal function, this pathway could represent an important converging theme in HSP pathogenesis (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Allison R, Edgar JR, Pearson G, Rizo T, Newton T, Günther S, Berner F, Hague J, Connell JW, Winkler J, Lippincott-Schwartz J, Beetz C, Winner B, Reid E, Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. J. Cell Biol 216, 1337– 1355 (2017). 28389476 PMC5412567 source
- Interpretationown data
The decrease of CAV1 protein upon WASH complex depletion most likely occurs post-translationally.
“Taken together, these results indicate that the decrease of CAV1 protein upon WASH complex depletion most likely occurs post-translationally.”
Quote in the paperSubstantial claim - Interpretationown data
Impaired endosomal tubulation could be linked to SPG8 pathogenesis.
“These results suggest that impaired endosomal tubulation could be linked to SPG8 pathogenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Rests on an assumption: Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
- Interpretationown data
Aberrant CAV1-dependent, integrin-mediated cell adhesion might underlie the axon degeneration that occurs in SPG8 patients.
“Our results indicate that aberrant CAV1-dependent, integrin-mediated cell adhesion might underlie the axon degeneration that occurs in SPG8 patients.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Rests on an assumption: Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
- Interpretationown data
SPG8 could be associated with abnormalities in CAV1-dependent, integrin-mediated cell adhesion.
“Together, these results demonstrate that SPG8-associated mutant strumpellin proteins were defective in CAV1-dependent, integrin-mediated cell adhesion, suggesting that SPG8 could be associated with abnormalities in CAV1-dependent, integrin-mediated cell adhesion.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Rests on an assumption: Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
- Premisecitation
Heterozygous 1 bp del-A (p.Ile134fsThr137) mutations in CAV1 segregate with spastic paraparesis, spastic-ataxic gait, congenital cataracts and pigmentary retinopathy in a Brazilian family.
“Finally, a study identified heterozygous 1 bp del-A (p.Ile134fsThr137) mutations in CAV1 that segregate with spastic paraparesis, spastic-ataxic gait, congenital cataracts and pigmentary retinopathy in a Brazilian family (48), further buttressing the case for a CAV1-dependent HSP mechanism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Souza PVS, Bortholin T, Dias RB, Chieia MAT, Burlin S, Naylor FGM, Pinto WBVR, Oliveira ASB, New genetic causes for complex hereditary spastic paraplegia. J. Neurol. Sci 379, 283– 292 (2017). 28716262
- Interpretationreasoning
These findings provide a clear molecular link between WASHC5 mutations and impairment of CAV1- and integrin-mediated cell adhesion.
“These findings provide a clear molecular link between WASHC5 mutations and impairment of CAV1- and integrin-mediated cell adhesion, providing potentially important insights into the cellular pathogenesis of SPG8.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
- Rests on an assumption: Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
- Probably not a substantial claim. 8
- It may state two separate claims as one. 12
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationThe WASH complex functions in endocytic recycling, maintenance of endolysosomal network integrity, exocytosis, cell adhesion, and cell migration.
“The WASH complex functions in the endocytic recycling of various types of membrane proteins, maintenance of endolysosomal network integrity, exocytosis, cell adhesion, and cell migration (11-23).”
Quote in the paperSubstantial claim7 of 10 sources checked- cites [11] Derivery E, Sousa C, Gautier JJ, Lombard B, Loew D, Gautreau A, The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex. Dev. Cell 17, 712– 723 (2009). 19922875 source
The Results (page unavailable) show that WASH depletion impairs transferrin recycling and causes tubulation across several endosomal compartments, supporting a role in recycling and endosomal organization. Our copy does not establish recycling of various types of membrane proteins or functions in exocytosis, cell adhesion, or cell migration. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [12] Gomez TS, Billadeau DD, A FAM21-containing WASH complex regulates retromer-dependent sorting. Dev. Cell 17, 699– 711 (2009). 19922874 PMC2803077 source
The Results section on CI-MPR sorting shows that WASH regulates retromer-dependent transport of a membrane receptor from endosomes toward the Golgi, supporting a role in endosomal recycling. The paper does not establish the broader claims about maintenance of endolysosomal network integrity, exocytosis, cell adhesion, or cell migration; it also reports that WASH is dispensable for TCR and EGFR endocytosis. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [13] Zech T, Calaminus SDJ, Caswell P, Spence HJ, Carnell M, Insall RH, Norman J, Machesky LM, The Arp2/3 activator WASH regulates α5β1-integrin-mediated invasive migration. J. Cell Sci 124, 3753– 3759 (2011). 22114305 PMC3225265 source
The Introduction and the section ‘Integrin recycling is inhibited in WASH-depleted cells’ show that WASH regulates α5β1-integrin recycling and promotes invasive migration. This supports the recycling and migration portions of the claim, but the paper does not establish maintenance of endolysosomal network integrity, exocytosis, or cell adhesion as separate WASH functions. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [14] Carnell M, Zech T, Calaminus SD, Ura S, Hagedorn M, Johnson SA, May RC, Soldati T, Machesky LM, Insall RH, Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. J. Cell Biol 193, 831– 839 (2011). 21606208 PMC3105540 source
The Introduction (WASH; page not provided) describes WASH roles in endosomal recycling and reports endosome dispersal and tubulation after WASH depletion. The Results and discussion (WASH and V-ATPase recycling; page not provided) show that WASH enables lysosomes to mature before exocytosis. Our copy does not establish roles for WASH in cell adhesion or migration; its Introduction instead discusses migration in connection with SCAR/WAVE proteins. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [15] Gomez TS, Gorman JA, de Narvajas AA, Koenig AO, Billadeau DD, Trafficking defects in WASH-knockout fibroblasts originate from collapsed endosomal and lysosomal networks. Mol. Biol. Cell 23, 3215– 3228 (2012). 22718907 PMC3418315 source
The Introduction and Discussion support roles for WASH in endosomal sorting and recycling of some membrane proteins, while the Results describe collapsed endosomal and lysosomal networks in WASH-knockout fibroblasts. The Introduction reports an exocytosis defect after WASH disruption in Dictyostelium, not in the fibroblasts studied here. Our copy does not establish a role in cell adhesion or migration; its report of integrin recycling does not itself demonstrate either function. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [16] Duleh SN, Welch MD, Regulation of integrin trafficking, cell adhesion, and cell migration by WASH and the Arp2/3 complex. Cytoskeleton (Hoboken) 69, 1047– 1058 (2012). 23012235 PMC3582321 source
- cites [17] Steinberg F, Gallon M, Winfield M, Thomas EC, Bell AJ, Heesom KJ, Tavaré JM, Cullen PJ, A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nat. Cell Biol 15, 461– 471 (2013). 23563491 PMC4052425 source
The Discussion (page unavailable) links WASH to integrin trafficking and states that loss of WASH1 collapses endosomal and lysosomal networks, supporting roles in membrane-protein recycling and network integrity. A cited reference concerns WASH and invasive migration, but this paper does not itself establish the broader claims about cell migration or cell adhesion, and the passages do not address exocytosis. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [18] Bartuzi P, Billadeau DD, Favier R, Rong S, Dekker D, Fedoseienko A, Fieten H, Wijers M, Levels JH, Huijkman N, Kloosterhuis N, van der Molen H, Brufau G, Groen AK, Elliott AM, Kuivenhoven JA, Plecko B, Grangl G, McGaughran J, Horton JD, Burstein E, Hofker MH, van de Sluis B, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat. Commun 7, 10961 (2016). 26965651 PMC4792963 source
The Abstract describes WASH-dependent sorting of various transmembrane proteins, and the Results (‘COMMD1 and WASH facilitate LDLR trafficking’; page not provided) report endosomal collapse after WASH loss. These passages support the recycling and endolysosomal-integrity portions, but our copy does not substantiate the listed roles in exocytosis, cell adhesion, or cell migration. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [19] Lee S, Chang J, Blackstone C, FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus. Nat. Commun 7, 10939 (2016). 26956659 PMC4786876 source
- cites [20] Tyrrell BJ, Woodham EF, Spence HJ, Strathdee D, Insall RH, Machesky LM, Loss of strumpellin in the melanocytic lineage impairs the WASH Complex but does not affect coat colour. Pigment Cell Melanoma Res. 29, 559– 571 (2016). 27390154 PMC5082549 source
It may state two separate claims as one.
Findingown dataDepletion of strumpellin abolishes α5 integrin localization at focal adhesions and increases intracellular α5 integrin.
“However, depletion of strumpellin mostly abolished α5 integrin localization at focal adhesions, as also shown previously in WASH1-depleted cells (13, 16); the intracellular pool of α5 integrin increased (Fig. 5A, arrows), reflecting a failure in integrin recycling (35).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingreasoningExpression of SPG8-associated strumpellin mutants impairs fission of endosomal tubules and maintenance of CAV1 protein levels.
“Altogether, these results indicate that expression of SPG8-associated strumpellin mutants impaired fission of endosomal tubules and maintenance of CAV1 protein levels.”
Quote in the paperSubstantial claim- Rests on an assumption: The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
- Rests on an assumption: Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
It may state two separate claims as one.
Findingown dataDepletion of strumpellin or WASH1 decreases total CAV1 protein levels.
“Total amounts of CAV1 were greatly decreased upon depletion of either strumpellin or WASH1 (Fig. 2, A and B).”
- Also stated in: § Maintenance of CAV1 protein levels depends on the WASH complex · plain
“Overall, total fluorescence intensities for CAV1 were reduced to about half of that in control cells, as also seen by immunoblotting (Fig. 2D).”
Quote in the paperSubstantial claim- Also stated in: § Maintenance of CAV1 protein levels depends on the WASH complex · plain
It may state two separate claims as one.
Findingown dataA strumpellin deletion mutant deficient in CAV1 binding fails to rescue the reduction in α5 integrin protein abundance caused by depletion of endogenous strumpellin, whereas wild-type strumpellin rescues.
“Whereas the expression of wild-type strumpellin rescued the reduction in α5 integrin protein abundance caused by the depletion of endogenous strumpellin, the strumpellin deletion mutant that was deficient in CAV1 binding failed to rescue (Fig. 6, C and D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataDepletion of strumpellin or WASH1 abolishes CAV1 signals at intracellular vesicles while plasma membrane CAV1 remains robust.
“Fluorescence signals for CAV1 at intracellular vesicles were also abolished in strumpellin- or WASH1-depleted cells, whereas CAV1 signals at the plasma membrane remained robust (Fig. 2C).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationreasoningDifferent types of strumpellin mutations could be linked to distinct clinical phenotypes.
“Thus, it seems likely that different types of strumpellin mutations could be linked to distinct clinical phenotypes.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenQuantitative real-time PCR experiments were performed in quadruplicate using three independent cDNAs.
“Experiments were performed in quadruplicate using three independent cDNAs.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOne patient sample with the c.3335+2T>A WASHC5 mutation showed a 60% reduction in strumpellin protein.
“one patient sample showed a 60% reduction in strumpellin protein”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Elliott AM, Simard LM, Coghlan G, Chudley AE, Chodirker BN, Greenberg CR, Burch T, Ly V, Hatch GM, Zelinski T, A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort. J. Med. Genet 50, 819– 822 (2013). 24065355 source
It may state two separate claims as one.
Premiseown dataEight of eleven pathogenic SPG8 mutations are located in the central spectrin domain of strumpellin, and five of those are between residues 608 and 790.
“Eight of eleven mutations identified in SPG8 patients localize to the spectrin-repeat domain, suggesting that this region could be particularly critical for SPG8 pathogenesis (8, 25, 32).”
- Also stated in: § Integrin recycling is mediated by an interaction between strumpellin and CAV1 · plain
“Eight of eleven pathogenic SPG8 mutations are located in the central spectrin domain of strumpellin, and five of those mutations are located between residues 608 and 790 within this domain (Fig. 4A).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Ichinose Y, Koh K, Fukumoto M, Yamashiro N, Kobayashi F, Miwa M, Nagasaka T, Shindo K, Ishiura H, Tsuji S, Takiyama DY, Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8. Clin. Neurol. Neurosurg 144, 36– 38 (2016). 26967522 source
- cites [25] Ma L, Shi Y, Chen Z, Li S, Qin W, Zhang J, A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: a case report. Medicine (Baltimore) 97, e10760 (2018). 29768361 PMC5976306 source
- cites [32] Jahic A, Khundadze M, Jaenisch N, Schüle R, Klimpe S, Klebe S, Frahm C, Kassubek J, Stevanin G, Schöls L, Brice A, Hübner CA, Beetz C, The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. Orphanet J. Rare Dis 10, 147 (2015). 26572744 PMC4647479 source
- Also stated in: § Integrin recycling is mediated by an interaction between strumpellin and CAV1 · plain
It may state two separate claims as one.
PremisecitationMice deficient in Cav1 have neurologic motor phenotypes including clasping, abnormal spinning, muscle weakness, and gait abnormalities.
“Furthermore, mice deficient in Cav1 have neurologic motor phenotypes including clasping, abnormal spinning, muscle weakness, and gait abnormalities (47), confirming the importance of CAV1 in motor function.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] Trushina E, Du Charme J, Parisi J, McMurray CT, Neurological abnormalities in caveolin-1 knock out mice. Behav. Brain Res 172, 24– 32 (2006). 16750274 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA biallelic splice-site mutation at the C-terminus of WASHC5 has been reported in numerous members of a First Nations community in northern Manitoba, Canada who have Ritscher-Schinzel/3C syndrome (RSS), a disorder characterized by distinctive craniofacial features as well as cerebellar and cardiac abnormalities.
“A biallelic splice-site mutation at the C-terminus has been reported in numerous members of a First Nations community in northern Manitoba, Canada with Ritscher-Schinzel/3C syndrome (RSS), a disorder characterized by distinctive craniofacial features as well as cerebellar and cardiac abnormalities (50).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Elliott AM, Simard LM, Coghlan G, Chudley AE, Chodirker BN, Greenberg CR, Burch T, Ly V, Hatch GM, Zelinski T, A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort. J. Med. Genet 50, 819– 822 (2013). 24065355 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe animal studies were approved by the NINDS/NIDCD Animal Care and Use Committee.
“Animal studies were approved by the NINDS/NIDCD Animal Care and Use Committee.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationgnomAD lists dozens of frameshift or stop gain mutations in WASHC5, plus numerous splice site mutations, in normal subjects, which argues against haploinsufficiency as a disease mechanism for SPG8.
“though the Genome Aggregation Database (gnomAD; https://gnomad.broadinstitute.org) lists dozens of frameshift or stop gain mutations in WASHC5, plus numerous splice site mutations, in normal subjects, which would argue strongly against haploinsufficiency as a disease mechanism for SPG8.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites gnomAD
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
PremisecitationDepletion of strumpellin in zebrafish impairs motility, and siRNA knockdown in human neuroblastoma SH-SY5Y cells reduces neurite length.
“On the other hand, depletion of strumpellin in zebrafish impairs motility, and siRNA knockdown in human neuroblastoma SH-SY5Y cells reduces neurite length (38).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Clemen CS, Tangavelou K, Struckberg K-H, Just S, Gaertner L, Regus-Leidig H, Stumpf M, Reimann J, Coras R, Morgan RO, Fernandez M-P, Hofmann A, Müller S, Schoser B, Hanisch F-G, Rottbauer W, Blümcke I, von Hörsten S, Eichinger L, Schröder R, Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. Brain 133, 2920– 2941 (2010). 20833645 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll DNA constructs used in this study were confirmed by DNA sequencing.
“All constructs were confirmed by DNA sequencing.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataOnly integrin localization was altered upon strumpellin depletion, suggesting strumpellin specifically affects CAV1-mediated sorting pathways.
“Only integrin localization was altered upon strumpellin depletion, suggesting that strumpellin specifically affects CAV1-mediated sorting pathways (Fig. 5, A and E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationHeterozygous WASHC5+/− mice do not show HSP-related phenotypes, suggesting heterozygous loss of SPG8 might not lead to haploinsufficiency.
“Furthermore, heterozygous WASHC5+/− mice do not show HSP-related phenotypes, suggesting heterozygous loss of SPG8 might not lead to haploinsufficiency (32).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Jahic A, Khundadze M, Jaenisch N, Schüle R, Klimpe S, Klebe S, Frahm C, Kassubek J, Stevanin G, Schöls L, Brice A, Hübner CA, Beetz C, The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. Orphanet J. Rare Dis 10, 147 (2015). 26572744 PMC4647479 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe WASHC5 mutation c.3335+2T>A results in skipping of exon 27 near the C-terminus.
“This mutation, c.3335+2T>A, results in skipping of exon 27 near the C-terminus”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Elliott AM, Simard LM, Coghlan G, Chudley AE, Chodirker BN, Greenberg CR, Burch T, Ly V, Hatch GM, Zelinski T, A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort. J. Med. Genet 50, 819– 822 (2013). 24065355 source
The authors state this as an assumption.
Little is known about how SPG8-associated mutations in WASHC5 cause HSP.
“Although the WASH complex has been extensively studied, little is known about how SPG8-associated mutations in WASHC5 cause HSP.”
The authors state this as an assumption.
Various other cellular roles for strumpellin do not account for how SPG8-associated mutations lead to HSP.
“Although various other cellular roles for strumpellin have also been described, none account for how SPG8-associated mutations lead to HSP.”
The paper relies on this without support.
The four SPG8 missense mutants tested (N471D, L619F, V626F, G696A) are representative of pathogenic SPG8 mutations.
“Thus, we chose four missense mutations within this domain (N471D, L619F, V626F, and G696A) for further analysis (Fig. 4A).”
The paper relies on this without support.
Depleting endogenous strumpellin and expressing SPG8 mutant proteins in hTERT-RPE1 cells models the cellular effects of autosomal dominant SPG8 mutations.
“To assess the characteristics of autosomal dominant mutations in WASHC5 at the cellular level, we generated hTERT-RPE1 cells stably expressing strumpellin proteins harboring known SPG8-associated missense mutations along with silent mutations rendering them resistant to siRNA-mediated knockdown.”
The paper relies on this without support.
Cellular phenotypes in hTERT-RPE1 cells and cultured rat cortical neurons reflect mechanisms of HSP axonopathy in patients.
“In cultured rat cerebral cortical neurons depleted of strumpellin using short hairpin RNAs (shRNAs), a similar reduction in CAV1 abundance occurred, suggesting that this reduction may be relevant for SPG8 pathogenesis (Fig. 2, E and F).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Pathogenic WASHC5 mutations in strumpellin can induce defects in endosomal fission or lysosome morphology, which further leads to HSP.
“Pathogenic WASHC5 mutations in strumpellin can induce defects in endosomal fission or lysosome morphology, which further leads to HSP (Lee et al., 2020; Song et al., 2018).”
From Case report: A novel WASHC5 variant altering mRNA splicing causes spastic paraplegia in a patient (2023) · cites this paper as Lee et al., 2020
Abnormal strumpellin may lead to defects in the endosomal and lysosomal systems.
“Furthermore, the abnormal strumpellin may lead to defects in the endosomal and lysosomal systems (Gomez et al., 2012; Lee et al., 2020; Song et al., 2018).”
From Case report: A novel WASHC5 variant altering mRNA splicing causes spastic paraplegia in a patient (2023) · cites this paper as Lee et al., 2020
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
WASHC5 is given two different KIAA identifiers
MinorThe abstract and Methods identify WASHC5 as KIAA0196, but the Introduction identifies it as KIAA1096.
“WASHC5 (also known as KIAA0196)”
“WASHC5 (also known as KIAA1096)”
Spectrin-repeat domain has inconsistent endpoint
MinorThe Introduction defines the spectrin-repeat domain as ending at residue 791, while the Results define it as ending at residue 790.
“a central spectrin-repeat domain (five repeats, each comprising three α-helices; residues 241-791)”
“the central spectrin-repeat domain of strumpellin (residues 241-790)”
Citations
Cites
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190
The multiple faces of caveolae
Parton, R. G., & Simons, K. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2122 · Cited by 1,456
Oh, P., McIntosh, D. P., & Schnitzer, J. E. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.1.101 · Cited by 677
The Arp2/3 Activator WASH Controls the Fission of Endosomes through a Large Multiprotein Complex
Derivery, E., Sousa, C., Gautier, J. J., Lombard, B., Loew, D., & Gautreau, A. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.09.010 · Cited by 602
Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., et al. (2014) · Science · doi:10.1126/science.1247363 · Cited by 538
Steinberg, F., Gallon, M., Winfield, M., Thomas, E. C., Bell, A. J., Heesom, K. J., Tavaré, J. M., & Cullen, P. J. (2013) · Nature Cell Biology · doi:10.1038/ncb2721 · Cited by 524
A FAM21-Containing WASH Complex Regulates Retromer-Dependent Sorting
Gomez, T. S., & Billadeau, D. D. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.09.009 · Cited by 521
New insights into the regulation and cellular functions of the ARP2/3 complex
Rotty, J. D., Wu, C., & Bear, J. E. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3492 · Cited by 516
Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms
Fink, J. K. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1115-8 · Cited by 481
Retromer: A Master Conductor of Endosome Sorting
Burd, C., & Cullen, P. J. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016774 · Cited by 435
Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization
del Pozo, M. Á., Balasubramanian, N., Alderson, N. B., Kiosses, W. B., Grande-García, A., Anderson, R. G. W., & Schwartz, M. A. (2005) · Nature Cell Biology · doi:10.1038/ncb1293 · Cited by 424
Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling
McNally, K. E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C. M., Nägele, H., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3610 · Cited by 346
Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation
Hayer, A., Stoeber, M., Ritz, D., Engel, S., Meyer, H. H., & Helenius, A. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201003086 · Cited by 298
Endocytic Trafficking of Integrins in Cell Migration
Paul, N. R., Jacquemet, G., & Caswell, P. T. (2015) · Current Biology · doi:10.1016/j.cub.2015.09.049 · Cited by 288
Regulation of WASH-Dependent Actin Polymerization and Protein Trafficking by Ubiquitination
Hao, Y.-H., Doyle, J., Ramanathan, S., Gomez, T. S., Jia, D., Xu, M., Chen, Z. J., Billadeau, D. D., Rosen, M. K., & Potts, P. R. (2013) · Cell · doi:10.1016/j.cell.2013.01.051 · Cited by 248
Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover
Shi, F., & Sottile, J. (2008) · Journal of Cell Science · doi:10.1242/jcs.014977 · Cited by 246
Caveolae: One Function or Many?
Cheng, J. P. X., & Nichols, B. J. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.010 · Cited by 242
Jia, D., Gomez, T. S., Metlagel, Z., Umetani, J., Otwinowski, Z., Rosen, M. K., & Billadeau, D. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913293107 · Cited by 232
Ritz, D., Vuk, M., Kirchner, P., Bug, M., Schütz, S., Hayer, A., Bremer, S., Lusk, C., Baloh, R. H., Lee, H., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2301 · Cited by 224
Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks
de Souza, P. V. S., Pinto, W. B. V. D. R., Batistella, G. N. D. R., Bortholin, T., & Oliveira, A. S. B. (2016) · The Cerebellum · doi:10.1007/s12311-016-0803-z · Cited by 221
Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation
Chang, J., Lee, S., & Blackstone, C. D. (2014) · Journal of Clinical Investigation · doi:10.1172/jci77598 · Cited by 210
Self-citationPol, A., Martin, S., Fernandez-Rojo, M. A., Ingelmo‐Torres, M., Ferguson, C., Enrich, C., & Parton, R. G. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-08-0737 · Cited by 207
CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
Bartuzi, P., Billadeau, D. D., Favier, R., Rong, S., Dekker, D., Fedoseienko, A., Fieten, H., Wijers, M., Levels, J. H., Huijkman, N., et al. (2016) · Nature Communications · doi:10.1038/ncomms10961 · Cited by 205
Mutations in the KIAA0196 Gene at the SPG8 Locus Cause Hereditary Spastic Paraplegia
Valdmanis, P. N., Meijer, I. A., Reynolds, A., Lei, A., MacLeod, P., Schlesinger, D., Zatz, M., Reid, E., Dion, P. A., Drapeau, P., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/510782 · Cited by 182
Defects in ER–endosome contacts impact lysosome function in hereditary spastic paraplegia
Allison, R., Edgar, J. R., Pearson, G., Rizo, T., Newton, T., Günther, S., Berner, F., Hague, J., Connell, J. W., Winkler, J., et al. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201609033 · Cited by 171
Gomez, T. S., Gorman, J. A., Artal-Martinez de Narvajas, A., Koenig, A. O., & Billadeau, D. D. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-02-0101 · Cited by 161
The caveolae dress code: structure and signaling
Lamaze, C., Tardif, N., Dewulf, M., Vassilopoulos, S., & Blouin, C. M. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.014 · Cited by 160
Carnell, M., Zech, T., Calaminus, S. D., Ura, S., Hagedorn, M., Johnston, S. A., May, R. C., Soldati, T., Machesky, L. M., & Insall, R. H. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009119 · Cited by 159
Zhu, P.-P., Patterson, A. D., Lavoie, B. A., Stadler, J., Shoeb, M., Patel, R. P., & Blackstone, C. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306702200 · Cited by 153
Self-citationTesson, C., Koht, J. A., & Stévanin, G. (2015) · Human Genetics · doi:10.1007/s00439-015-1536-7 · Cited by 149
Blackstone, C. D. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64076-5.00041-7 · Cited by 148
Self-citationThe Arp2/3 activator WASH regulates α5β1-integrin-mediated invasive migration
Zech, T., Calaminus, S. D. J., Caswell, P., Spence, H. J., Carnell, M., Insall, R. H., Norman, J., & Machesky, L. M. (2011) · Journal of Cell Science · doi:10.1242/jcs.080986 · Cited by 138
Converging cellular themes for the hereditary spastic paraplegias
Blackstone, C. D. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2018.04.025 · Cited by 130
Self-citationZhu, P. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl054 · Cited by 124
Self-citationHu, Z., Yu, D., Gu, Q.-H., Yang, Y., Tu, K., Zhu, J., & Li, Z. (2014) · Nature Communications · doi:10.1038/ncomms4263 · Cited by 122
RME-8 coordinates the WASH complex with the retromer SNX-BAR dimer to control endosomal tubulation
Freeman, C., Hesketh, G. G., & Seaman, M. N. J. (2014) · Journal of Cell Science · doi:10.1242/jcs.144659 · Cited by 117
Novel Locus for Autosomal Dominant Hereditary Spastic Paraplegia, on Chromosome 8q
Hedera, P., Rainier, S. R., Alvarado, D. M., Zhao, X., Williamson, J., Otterud, B., Leppert, M., & Fink, J. K. (1999) · The American Journal of Human Genetics · doi:10.1086/302258 · Cited by 110
Clinical and genetic study of hereditary spastic paraplegia in Canada
Chrestian, N., Dupré, N., Gan‐Or, Z., Szuto, A., Chen, S., Venkitachalam, A., Brisson, J., Warman‐Chardon, J., Ahmed, S., Ashtiani, S., et al. (2016) · Neurology Genetics · doi:10.1212/nxg.0000000000000122 · Cited by 104
Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons
Head, B. P., Hu, Y., Finley, J. C., Saldana, M., Bonds, J. A., Miyanohara, A., Niesman, I. R., Ali, S. S., Murray, F., Insel, P. A., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.255976 · Cited by 96
Hereditary spastic paraplegia caused by a mutation in the VCP gene
de Bot, S. T., Schelhaas, H. J., Kamsteeg, E., & van de Warrenburg, B. P. C. (2012) · Brain · doi:10.1093/brain/aws201 · Cited by 80
cAMP-Dependent Axon Guidance Is Distinctly Regulated by Epac and Protein Kinase A
Murray, A. J., Tucker, S. J., & Shewan, D. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3071-09.2009 · Cited by 80
Neurological abnormalities in caveolin-1 knock out mice
Trushina, E., Du Charme, J., Parisi, J., & McMurray, C. T. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.04.024 · Cited by 76
Lee, S., Chang, J., & Blackstone, C. (2016) · Nature Communications · doi:10.1038/ncomms10939 · Cited by 73
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Elliott, A. M., Simard, L. R., Coghlan, G., Chudley, A. E., Chodirker, B. N., Greenberg, C. R., Burch, T., Ly, V., Hatch, G. M., & Zelinski, T. (2013) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2013-101715 · Cited by 70
Singer, H. S., Mink, J. W., Gilbert, D. L., & Jankovic, J. J. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-820552-5.00021-8 · Cited by 67
Kirchner, P., Bug, M., & Meyer, H. H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.429076 · Cited by 56
Kvainickas, A., Orgaz, A. J., Nägele, H., Diedrich, B., Heesom, K. J., Dengjel, J., Cullen, P. J., & Steinberg, F. (2016) · Journal of Cell Science · doi:10.1242/jcs.196758 · Cited by 53
Freeman, C., Seaman, M. N. J., & Reid, E. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.10.011 · Cited by 50
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Burana, D., Yoshihara, H., Tanno, H., Yamamoto, A., Saeki, Y., Tanaka, K., & Komada, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.710707 · Cited by 27
Bettencourt, C., Morris, H. R., Singleton, A., Hardy, J., & Houlden, H. (2013) · Journal of Neurology · doi:10.1007/s00415-013-7044-6 · Cited by 22
Tyrrell, B. J., Woodham, E. F., Spence, H. J., Strathdee, D., Insall, R. H., & Machesky, L. M. (2016) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12506 · Cited by 21
Jahic, A., Khundadze, M., Jaenisch, N., Schüle, R., Klimpe, S., Klebe, S., Frahm, C., Kassubek, J., Stevanin, G., Schöls, L., et al. (2015) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-015-0359-x · Cited by 17
Ichinose, Y., Koh, K., Fukumoto, M., Yamashiro, N., Kobayashi, F., Miwa, M., Nagasaka, T., Shindo, K., Ishiura, H., Tsuji, S., et al. (2016) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2016.02.031 · Cited by 11
A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A case report
Ma, L., Shi, Y., Chen, Z., Li, S., Qin, W., & Zhang, J. (2018) · Medicine · doi:10.1097/md.0000000000010760 · Cited by 7
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Clemen, C. S., Schmidt, A., Winter, L., Canneva, F., Wittig, I., Becker, L., Coras, R., Berwanger, C., Hofmann, A., Eggers, B., et al. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12750 · Cited by 10
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Park, H., Park, J., Kim, T., Heo, H., Chang, J., Blackstone, C. D., & Lee, S. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04897-3 · Cited by 5
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Wei, L., Hu, S., Gong, X., Ahemaiti, Y., Li, D., Ouyang, S., Huang, Y., Wang, Y., Liang, Y., Deng, Y., et al. (2025) · Gene · doi:10.1016/j.gene.2025.149351
Metadata
- Authors
- Lee, S., Park, H., Zhu, P.-P., Jung, S.-Y., Blackstone, C., & Chang, J.
- Affiliations
- National Institutes of Health (US)
- Inha University (KR)
- Ajou University (KR)
- Corresponding author
- Blackstone, Craig
- Chang, Jaerak
- Venue
- Science Signaling
- Published
- 2020-01-07
- Volume
- 13
- Issue
- 613
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC7231525
- OpenAlex
- W3000627564
- Cited by
- 22
- References
- 58
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 7 · 2022: 1 · 2021: 6 · 2020: 4
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS003128)
- National Research Foundation of Korea (NRF-2016R1A6A3A04006478, NRF-2014R1A5A2009392, NRF-2019R1F1A1051699, NRF-2019R1A5A2026045)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- hereditary spastic paraplegia, caveolin-1, integrins, cell adhesion, genetic mutations, cellular pathogenesis
- MeSH terms
- Animals, Cell Adhesion, Humans, Lysosomes, Mutation, Paraplegia, Proteins, Spastic Paraplegia, Hereditary, Integrins, Caveolin 1, Rats, HEK293 Cells, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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