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Cited by 0Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyMicroRNA in disease regulation

miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A

Open access
Markham, Briana N., Ramnarine, Chloe, Kim, Songeun, Grever, William E., Soto-Beasley, Alexandra I., Heckman, Michael G., Ren, Yingxue, Osborne, Andrew C. +9 more·2026·Molecular Neurodegeneration Advances
DOI 10.1186/s44477-026-00029-wPMC PMC13275600
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Abstract

Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together, the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high-content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). RNA sequencing revealed target genes regulated by miR-29 and identified ATG9A as a candidate gene. SiRNA-mediated ATG9A silencing phenocopied the effects of miR-29 and suppressed the initiation of PINK1-PRKN–mediated mitophagy. In addition, expression of ATG9A was able to rescue the effects of miR-29a, suggesting that ATG9A is primarily responsible for the inhibitory effect of miR-29. In an EOPD patient cohort, we further discovered two rare, potentially deleterious, ATG9A missense variants (p.R631W and p.S828L) and tested them experimentally in cells. Strikingly, neither EOPD ATG9A variant was able to rescue the phenotype suggesting they both act as loss-of-function mutations and might contribute to the etiology of disease. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of PINK1-PRKN signaling. It further serves as proof-of-concept with the identification of novel, potentially disease-relevant EOPD variants specifically in mitophagy-regulating genes. The nomination of biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.

AI snapshot

Written from the paper’s full text.

TL;DR

A genome-wide miRNA screen identified all three miR-29 family members as inhibitors of PINK1-PRKN–dependent mitophagy, acting primarily through the target gene ATG9A. In an early-onset Parkinson disease cohort, two rare ATG9A missense variants failed to rescue the phenotype, suggesting loss-of-function contributions to disease etiology.

Key findings

  • Screening 1902 miRNAs found 81 miRNAs (4.3%) that reduced PRKN translocation to under 50%; all three miR-29 members were hits, and 20 of 81 were confirmed using an independent miRNA library.
  • RNA sequencing after miR-29a transfection identified 146 differentially expressed genes (adjusted p < 0.01), 84% of which were downregulated; 78 overlapped with TargetScan miR-29a predictions, and ATG9A was prominently changed.
  • miR-29 transfection reduced ATG9A protein to about 40%–70% depending on condition; ATG9A siRNA reduced ATG9A protein by about 90%, reduced GFP-PRKN translocation by 50% at 2 h, and strongly reduced CCCP-induced mitophagy. Re-expression of wild-type ATG9A rescued PRKN translocation after miR-29a.
  • In 208 EOPD cases with onset before age 50, two rare heterozygous ATG9A missense variants were found, p.R631W and p.S828L; both had low gnomAD allele frequency and CADD scores among the most 1% deleterious, and neither rescued PRKN translocation compared with wild-type ATG9A.

Methods

  • Genome-wide high-content imaging miRNA screen in HeLa cells stably expressing GFP-PRKN, using 1902 miRNAs, 3.5 µM CCCP for 2 h, and a machine-learning classifier; hits were validated with independent reagents and 10 µM CCCP.
  • RNA sequencing in HeLa cells (n = 3 per group) comparing control miRNA and miR-29a, analyzed with MAP-Rseq and edgeR at adjusted p < 0.01; follow-up included qRT-PCR, western blot, mitoKeima live imaging, TMRM, and pS65-Ub ELISA.
  • Genetic screening used whole-genome sequencing from 150 Mayo Clinic EOPD samples and 58 PPMI EOPD patients (208 total), focusing on rare exonic ATG9A variants, followed by functional rescue experiments in HeLa cells.

Limitations

  • The paper states that the exact mechanisms by which ATG9A interferes with PINK1 stabilization remain unresolved, and that whether heterozygous ATG9A variants are linked to EOPD pathogenesis remains to be determined; further genetic studies and biospecimens from ATG9A mutation carriers are warranted.
  • Evident from the text: most functional work uses HeLa cell overexpression models rather than patient-derived neurons, and the genetic finding rests on two rare variants in a 208-person EOPD cohort without segregation or patient biospecimen validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s44477-026-00029-w

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

61 of 74 cited sources checked · 25 supported · 4 flagged · accuracy not yet measured

  • Premisecitation

    Multiple genome-wide siRNA/CRISPR-Cas9 screens have identified mitophagy genes with little overlap between studies.

    “Multiple genome-wide siRNA/CRISPR-Cas9 screens have already identified mitophagy genes although with little overlap between studies [15–18].”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [15] Ivatt RM, Sanchez-Martinez A, Godena VK, et al. Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc Natl Acad Sci U S A. 2014;111(23):8494–9. source

      The RNAi Screening section (page not provided) describes a genome-wide Drosophila RNAi screen and subsequent human-cell siRNA validation that identified 20 candidate mitophagy genes. It does not compare its hits with those of other studies or establish that overlap between screens was small; it also does not report a CRISPR-Cas9 screen. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [16] Hasson SA, Kane LA, Yamano K, et al. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature. 2013;504(7479):291–5. source

      The paper reports genome-wide siRNA screens that identified regulators of parkin upstream of mitophagy (conclusion, page unavailable). Its candidate-selection passage says 24 candidates overlapped between its own pooled and non-pooled screens, but it does not establish little overlap between different studies; it also does not report a CRISPR-Cas9 screen. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [17] McCoy MK, Kaganovich A, Rudenko IN, et al. Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet. 2014;23(1):145–56. source

      The high-content screen section describes a genome-wide shRNA screen that identified HK2 as a modifier of parkin recruitment before mitophagy, so this paper supports the cited group of studies as an example of a gene-finding screen. It used shRNA rather than siRNA or CRISPR-Cas9, and our copy does not establish that the genes identified by different screens had little overlap. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [18] Hoshino A, Wang WJ, Wada S, et al. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature. 2019;575(7782):375–9. source

      The paper reports its own genome-wide CRISPR/Cas9 mitophagy screen (Abstract; page unavailable) and cites an earlier genome-wide RNAi screen (References; page unavailable). It reports variability among assays within its own study, but does not establish that different studies identified genes with little overlap. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    Transfection of miR-27b caused impaired PRKN translocation.

    “transfection of miR-27b caused impaired PRKN translocation, in line with our previous description [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Kim J, Fiesel FC, Belmonte KC, et al. miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). Mol Neurodegener. 2016;11(1):55. source
  • Premisecitation

    PINK1 and PRKN direct a neuroprotective pathway that ensures elimination of damaged mitochondria via autophagy.

    “Together, the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy.”
    • Also stated in: § Introduction · plain
      “PINK1 and PRKN are at the center of a mitophagy pathway that eliminates damaged mitochondria through autophagy [3, 4]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] Geisler S, Holmstrom KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31. source
    • cites [4] Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8(1):e1000298. source

      The Introduction (page unavailable) reports that PINK1 is required for Parkin recruitment to depolarized mitochondria and subsequent mitophagy. It describes the pathway’s role in preventing parkinsonism as consistent with a model, while the Discussion (page unavailable) says the pathway may promote damaged-mitochondrion turnover. Calling it neuroprotective and saying it “ensures” elimination states that proposed protective effect more definitively than the paper does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    Of the five miRNAs experimentally confirmed to directly target PINK1, only miR-27b was among the top hits in the genome-wide screen.

    “However, of the five miRNAs that have been experimentally confirmed to directly target PINK1 [37–39], only miR-27b [32] was among the top hits in our genome-wide screen.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [37] Tai Y, Pu M, Yuan L, et al. miR-34a-5p regulates PINK1-mediated mitophagy via multiple modes. Life Sci. 2021;1(276):119415. source
    • cites [38] Qiu F, Wu Y, Xie G, et al. MiRNA-1976 Regulates the apoptosis of dopaminergic neurons by targeting the PINK1 gene. J Integr Neurosci. 2023;22(2):45. source

      Section 3.3 reports a luciferase assay showing that miR-1976 directly binds the PINK1 3′-UTR, supporting its inclusion among experimentally confirmed PINK1-targeting miRNAs. This paper does not establish that there are five such miRNAs in total. The genome-wide-screen finding is separately attributed to citation [32], not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [39] Yoo M, Choi DC, Murphy A, et al. MicroRNA-593-5p contributes to cell death following exposure to 1-methyl-4-phenylpyridinium (MPP(+)) by targeting PTEN-induced putative kinase 1 (PINK1). J Biol Chem. 2023;13:104709. source
    • cites [32] Kim J, Fiesel FC, Belmonte KC, et al. miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). Mol Neurodegener. 2016;11(1):55. source
  • Premisecitation

    miR-29b and miR-29c share a tri-uracil element at nucleotide positions 9-11 that causes their rapid decay.

    “miR-29b and miR-29c share a tri-uracil element at nucleotide positions 9–11 that causes their rapid decay [43].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Zhang Z, Zou J, Wang GK, et al. Uracils at nucleotide position 9-11 are required for the rapid turnover of miR-29 family. Nucleic Acids Res. 2011;39(10):4387–95. source

      In Results (“Uracils at nucleotide position 9–11 of miR-29b are required for its rapid decay”; page unavailable), replacing those uracils stabilizes miR-29b, supporting their role in its rapid decay. Results (“A subset of miRNAs with uracils at nucleotide positions 9–11 possesses rapid turnover”; page unavailable) reports relatively rapid turnover for miR-29c, but does not establish that the element causes miR-29c’s decay. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 34
  • May combine two claims. 26
  • The quote only partly states this claim. 3

  • Classified as probably not a substantial claim.

    Premisecitation

    Phosphorylation of ubiquitin and PRKN at Ser65 by PINK1 is required for activation of the PINK1-PRKN pathway.

    “Both events are required for the activation of the pathway.”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [5] Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205(2):143–53. source

      The Results and discussion show that ubiquitin S65 phosphorylation contributes to Parkin activation, but explicitly state that Parkin S65 phosphorylation is not required for activation by phosphomimetic ubiquitin in cells. Parkin S65A also retained ubiquitination activity, so the paper contradicts the claim that both events are required. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [6] Kazlauskaite A, Kondapalli C, Gourlay R, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014;460(1):127–39. source

      The Results section on the dual requirement (page not provided) says phosphorylation of both Parkin and ubiquitin at Ser65 is required for optimal Parkin E3 ligase activation. It also reports that only mutation of both sites completely abolishes activity. The claim omits the 'optimal' qualifier and overstates the evidence by saying both events are required for activation at all. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [7] Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510(7503):162–6. source
    • cites [8] Kondapalli C, Kazlauskaite A, Zhang N, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2(5):120080. source

      The Results section reports that PINK1 phosphorylates Parkin (PRKN) at Ser65 and that a non-phosphorylatable Parkin S65A mutant does not show the observed E3 ligase activation. It does not establish that PINK1 phosphorylates ubiquitin at Ser65 or that ubiquitin phosphorylation is also required for pathway activation; ubiquitin is described as a component and product of the ubiquitylation assay. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [9] Shiba-Fukushima K, Imai Y, Yoshida S, et al. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep. 2012;2:1002. source

      The Abstract and Results report that PINK1-dependent phosphorylation of Parkin (PRKN) at Ser65 is important for its efficient mitochondrial translocation and mitophagy. Our copy does not establish that PINK1 phosphorylation of ubiquitin at Ser65 is also required; its references to a ubiquitin-like domain concern a domain of Parkin, not ubiquitin itself. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] Iguchi M, Kujuro Y, Okatsu K, et al. Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. J Biol Chem. 2013;288(30):22019–32. source

      The paper’s Parkin phosphorylation and ubiquitin-ester formation sections report that PINK1-dependent phosphorylation of Parkin at Ser65 is important for Parkin activation. They do not establish that PINK1 phosphorylation of ubiquitin at Ser65 is also required; the discussion only speculates that other PINK1 substrates may be involved. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondrial depolarization stabilizes PINK1 by arresting its import at the TOM complex, preventing turnover and allowing accumulation of full-length, dimerized PINK1 on the outer mitochondrial membrane.

    “Current models suggest that mitochondrial depolarization stabilizes PINK1 by arresting its import at the TOM complex, thereby preventing turnover and allowing accumulation of full-length, dimerized PINK1 on the outer mitochondrial membrane [59–62].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [59] Lazarou M, Jin SM, Kane LA, et al. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell. 2012;22(2):320–33. source

      The Results section reports that depolarization inhibits PINK1 import and degradation, allowing it to accumulate on the outer mitochondrial membrane. But the Discussion explicitly argues against the claim’s proposed mechanism of import stalling at the TOM complex; it says PINK1 can associate with TOM without impaired import. The Discussion also presents PINK1 dimerization as a possibility, not an established result. Page numbers were not available in our copy. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [60] Maruszczak KK, Jung M, Rasool S, et al. The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria. J Mol Med (Berl). 2022;100(5):747–62. source
    • cites [61] Kakade P, Ojha H, Raimi OG, et al. Mapping of a N-terminal alpha-helix domain required for human PINK1 stabilization, Serine228 autophosphorylation and activation in cells. Open Biol. 2022;12(1):210264. source

      The Introduction says that mitochondrial depolarization stabilizes full-length PINK1 at mitochondria, and the Discussion links stabilization to reduced proteolysis and association with the TOM complex (page numbers unavailable). The Results also report reduced cleavage after depolarization. Our copy does not establish that PINK1 accumulates specifically as a dimer on the outer mitochondrial membrane or that its import is arrested at the TOM complex. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [62] Callegari S, Kirk NS, Gan ZY, et al. Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science. 2025;388(6744):303–10. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A KO mice die at a very early developmental stage.

    “ATG9A KO mice die at a very early developmental stage [53, 54].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [53] Yamaguchi J, Suzuki C, Nanao T, et al. Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis. Autophagy. 2018;14(5):764–77. source
    • cites [54] Saitoh T, Fujita N, Hayashi T, et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A. 2009;106(49):20842–6. source

      The Results state that all Atg9a-knockout mice died within one day of delivery, not at an early developmental stage. The paper describes neonatal death after birth. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A-positive vesicles are thought to represent a major membrane source for autophagosome biogenesis.

    “ATG9A-positive vesicles are thought to represent a major membrane source for autophagosome biogenesis [49].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Yamamoto H, Kakuta S, Watanabe TM, et al. Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol. 2012;198(2):219–33. source

      The Discussion says that Atg9 vesicles contribute membrane during early autophagosome formation, but explicitly calls them unlikely to be major lipid suppliers and says other lipid sources must be considered. The paper studies yeast Atg9 vesicles, not specifically ATG9A-positive vesicles. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Loss-of-function mutations in PINK1 and PRKN result in early-onset Parkinson disease.

    “Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222. source
    • cites [2] Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta. 2010;1802(1):29–44. source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane and phosphorylates ubiquitin and PRKN at Ser65.

    “Upon mitochondrial depolarization, PINK1 stabilizes on the outer mitochondrial membrane, where it phosphorylates ubiquitin (Ub) and PRKN at Ser65 [5–10].”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [5] Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205(2):143–53. source
    • cites [6] Kazlauskaite A, Kondapalli C, Gourlay R, et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem J. 2014;460(1):127–39. source

      The Introduction says PINK1 becomes stabilized at mitochondria after membrane depolarization, and the Discussion’s Figure 9 model says activated PINK1 phosphorylates both Parkin (PRKN) and ubiquitin at Ser65. The copy does not specify that PINK1 stabilizes on the outer mitochondrial membrane, so that location is more specific than the cited paper supports. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Koyano F, Okatsu K, Kosako H, et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510(7503):162–6. source
    • cites [8] Kondapalli C, Kazlauskaite A, Zhang N, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2(5):120080. source

      The Introduction and Discussion report that depolarization stabilizes PINK1 at mitochondria and that PINK1 phosphorylates Parkin (PRKN) at Ser65. They describe relocation to the outer mitochondrial membrane as a proposal, not an established result. The Results discuss ubiquitin in ubiquitylation assays but do not show that PINK1 phosphorylates ubiquitin. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [9] Shiba-Fukushima K, Imai Y, Yoshida S, et al. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep. 2012;2:1002. source

      The Abstract reports that PINK1 accumulates on mitochondria after membrane-potential loss and that Parkin (PRKN) is phosphorylated at Ser65 in a PINK1-dependent manner. The Discussion reports direct phosphorylation of Parkin by PINK1 in vitro but says whether this occurs directly in cells remains unresolved. Our copy does not establish phosphorylation of ubiquitin at Ser65 or specify stabilization on the outer mitochondrial membrane. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] Iguchi M, Kujuro Y, Okatsu K, et al. Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. J Biol Chem. 2013;288(30):22019–32. source

      The Abstract says PINK1 localizes to mitochondria after escaping membrane-potential-dependent degradation and describes PINK1 phosphorylation of Parkin at Ser-65. The paper discusses ubiquitin attachment to Parkin, but the passages found do not say that PINK1 phosphorylates ubiquitin; that part of the citing sentence is unsupported by this source. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cytosolic PRKN translocates to mitochondria and contributes to formation of mitochondrial pS65-Ub chains.

    “Cytosolic PRKN translocates to mitochondria and contributes to the formation of mitochondrial pS65-Ub chains [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Truban D, Hou X, Caulfield TR, et al. PINK1, parkin, and mitochondrial quality control: what can we learn about Parkinson’s disease pathobiology? J Parkinsons Dis. 2017;7(1):13–29. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recessively inherited loss-of-function mutations in PINK1 and PRKN are the most common genetic causes of early-onset PD, which occurs in about 5%-10% of cases.

    “Recessively inherited loss-of-function mutations in PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase PRKN are the most common genetic causes for early-onset PD, which occurs in about 5%–10% of cases [1, 2].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222. source
    • cites [2] Winklhofer KF, Haass C. Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta. 2010;1802(1):29–44. source

      The Introduction identifies loss-of-function mutations in parkin (PRKN) and PINK1 as causes of autosomal recessive PD. Sections 2.1.1.1 and 2.1.2.1 describe PINK1 as the second most common cause of recessive early-onset parkinsonism after parkin, which accounts for the majority of recessive cases. Section 2.1 says familial PD accounts for up to 10% of PD cases and usually, but not always, has early onset; it does not establish that early-onset PD itself occurs in 5%–10% of cases. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Mitochondrial pS65-Ub chains serve as a specific signal for engulfment of mitochondria in autophagosomes.

    “These serve as a specific signal for the engulfment of mitochondria in autophagosomes [12].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309–14. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    pS65-Ub accumulates during aging, stress, and disease.

    “pS65-Ub has been shown to accumulate during aging, stress, and disease [13, 14]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Fiesel FC, Ando M, Hudec R, et al. (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Rep. 2015;16(9):1114–30. source
    • cites [14] Hou X, Fiesel FC, Truban D, et al. Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease. Autophagy. 2018;14(8):1404–18. source

  • Classified as probably not a substantial claim.

    Premisecitation

    ATG9A was previously identified as a regulator of PINK1-PRKN induced mitophagy in a CRISPR screen.

    “It was also previously identified as a regulator of PINK1-PRKN induced mitophagy in a CRISPR screen [18]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [18] Hoshino A, Wang WJ, Wada S, et al. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature. 2019;575(7782):375–9. source

      The paper describes a CRISPR screen for PINK1–Parkin-mediated mitophagy and says it identified autophagosome-related genes (main text and Extended Data Figures 1–2; pages unavailable). Searches for “ATG9A” and “Atg9 mitophagy CRISPR screen” found no passage identifying ATG9A as a screen hit, so our copy does not verify the specific claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The study used an established stable HeLa cell model with homogenous expression of GFP-PRKN.

    “we used an established stable HeLa cell model with homogenous expression of GFP-PRKN [19].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Fiesel FC, Moussaud-Lamodiere EL, Ando M, et al. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci. 2014;127(Pt 16):3488–504. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Successful transfection in the screen was confirmed by a killer siRNA that reduced cell count by 85%-90%.

    “Successful transfection was confirmed by a killer siRNA [23] which reduced the cell count by 85%–90%.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Egan DF, Chun MG, Vamos M, et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell. 2015;59(2):285–97. source

      The Results section on ULK1 siRNA describes a focused RNAi screen and control-siRNA-transfected cells, but does not describe a killer siRNA used to confirm transfection. Searches for “killer siRNA,” “cell count,” and “85%–90%” found no passage supporting the reported reduction. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy.

    “has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy [12, 34, 35].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [12] Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309–14. source

      The 'Autophagy receptors in mitophagy' section (page not provided) shows that OPTN helps mediate Parkin-associated mitophagy, redundantly with NDP52. Our copy does not establish a link between ATG9A and OPTN; ATG9A appears only in the title of a work listed in the References. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [34] Yamano K, Kikuchi R, Kojima W, et al. Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. J Cell Biol. 2020. https://doi.org/10.1083/jcb.201912144. source
    • cites [35] Heo JM, Ordureau A, Paulo JA, et al. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell. 2015;60(1):7–20. source

      The Discussion reports that PARKIN-mediated mitochondrial ubiquitylation recruits autophagy adaptors, including OPTN, and promotes mitophagy. That supports OPTN’s role in PINK1-PARKIN mitophagy, but the passages retrieved for ATG9A and OPTN do not establish a link between those two proteins. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductown data

    The machine-learning classifier had excellent agreement with the established GFP-PRKN ratio algorithm and a combined Z' score of 0.79.

    “There was excellent agreement between the new classifier and the established ‘GFP-PRKN ratio’ algorithm [19, 20, 25, 30] (Fig. 1C, Table S4) but the new classifier was more robust in this screening setting and had a combined Z’ score of 0.79.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [19] Fiesel FC, Moussaud-Lamodiere EL, Ando M, et al. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci. 2014;127(Pt 16):3488–504. source
    • cites [20] Fiesel FC, James ED, Hudec R, et al. Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. Oncotarget. 2017;8(63):106233–48. source
    • cites [25] Fiesel FC, Caulfield TR, Moussaud-Lamodiere EL, et al. Structural and functional impact of Parkinson disease-associated mutations in the E3 ubiquitin ligase Parkin. Hum Mutat. 2015;36(8):774–86. source
    • cites [30] Fiesel FC, Fricova D, Hayes CS, et al. Substitution of PINK1 Gly411 modulates substrate receptivity and turnover. Autophagy. 2022;5:1–22. source

      The Results section (‘PINK1G411A is a more active Ub kinase’; page unavailable) reports high-content quantification of GFP-PRKN translocation, and the high-content imaging Methods describe those measurements. Our copy does not identify a ‘GFP-PRKN ratio’ algorithm or report agreement with a machine-learning classifier or a combined Z′ score of 0.79. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Inactive ATG9A with mutations in the core part of the protein increased LC3 puncta size in ATG9A KO and wildtype HeLa cells, suggesting a dominant-negative effect.

    “a recent study found that inactive ATG9A with mutations in the core part of the protein increased LC3 puncta size not only in ATG9A KO but also in wildtype HeLa cells, suggesting a dominant-negative effect [65].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Guardia CM, Tan XF, Lian T, et al. Structure of human ATG9A, the only transmembrane protein of the core autophagy machinery. Cell Rep. 2020;31(13):107837. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ATG9A is not incorporated into autophagosomes and plays an essential role in their formation, expansion and closure.

    “ATG9A, which itself is not incorporated into autophagosomes, is known to play an essential role for their formation, expansion and closure [47, 48].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [47] Choi J, Jang H, Xuan Z, et al. Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology. Autophagy. 2024;4:1–15. source

      The 'Role of ATG9/ATG9A in autophagy' section says ATG9A is believed to interact with autophagosomes without being incorporated into them, and links it to phagophore expansion. The membrane-expansion models section also supports a role in early formation. The copy does not establish a role in autophagosome closure, and its wording is more tentative than 'is known to play an essential role' throughout. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [48] Javed R, Mari M, Trosdal E, et al. ATG9A controls all stages of autophagosome biogenesis. Autophagy. 2025;21(8):1859–61. source

      The Abstract and Figure 1 description say ATG9A contributes to phagophore initiation, expansion, and closure. They do not say that ATG9A is absent from completed autophagosomes, so the non-incorporation part is unsupported by our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-29a is the most abundantly expressed and stable among the miR-29 family.

    “miR-29a, which is the most abundantly expressed and stable among the family [43]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [43] Zhang Z, Zou J, Wang GK, et al. Uracils at nucleotide position 9-11 are required for the rapid turnover of miR-29 family. Nucleic Acids Res. 2011;39(10):4387–95. source

      The Results (Figure 3B and the section on rapid turnover) show that miR-29a is more stable than miR-29b and miR-29c in the authors’ HeLa-cell assay. The paper does not establish that miR-29a is the most abundantly expressed family member; its abundance measurements concern transfected miRNA mimickers rather than a comparison of endogenous family-member expression. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A acts as a lipid scramblase facilitating membrane expansion.

    “ATG9A was more recently shown to act as a lipid scramblase facilitating membrane expansion [50, 51].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [50] Maeda S, Yamamoto H, Kinch LN, et al. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Nat Struct Mol Biol. 2020;27(12):1194–201. source
    • cites [51] Matoba K, Kotani T, Tsutsumi A, et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. Nat Struct Mol Biol. 2020;27(12):1185–93. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    OPTN and NDP52 form dynamic condensates on damaged mitochondria.

    “recent work has begun to position ATG9A at earlier stages of selective mitophagy initiation, demonstrating that OPTN and NDP52 form dynamic condensates on damaged mitochondria.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] Yang Z, Yoshii SR, Sakai Y, et al. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates. EMBO J. 2024;43(22):5613–34. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A forms a homotrimer with a wide, solvated central pore and a lateral cavity.

    “ATG9A forms a homotrimer with a wide, solvated central pore and a lateral cavity [50].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Maeda S, Yamamoto H, Kinch LN, et al. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Nat Struct Mol Biol. 2020;27(12):1194–201. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A, together with IQGAP1 and ESCRT proteins, protects against plasma membrane damage.

    “Together with IQGAP1 and ESCRT proteins, ATG9A has further been shown to protect against plasma membrane damage [52].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Claude-Taupin A, Jia J, Bhujabal Z, et al. ATG9A protects the plasma membrane from programmed and incidental permeabilization. Nat Cell Biol. 2021;23(8):846–58. source

  • Classified as probably not a substantial claim.

    Premisecitation

    PINK1 stabilization on depolarized mitochondria results from impaired mitochondrial import and proteolytic processing, allowing full-length PINK1 to accumulate at the outer mitochondrial membrane.

    “PINK1 stabilization on depolarized mitochondria results from impaired mitochondrial import and proteolytic processing, allowing full-length PINK1 to accumulate at the outer mitochondrial membrane [57, 58].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [57] Jin SM, Lazarou M, Wang C, et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol. 2010;191(5):933–42. source
    • cites [58] Greene AW, Grenier K, Aguileta MA, et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012;13(4):378–85. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    OPTN recruits ATG9 vesicles to promote mitophagosome formation.

    “OPTN was further found to recruit ATG9 vesicles to promote mitophagosome formation [56].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] Yang Z, Yoshii SR, Sakai Y, et al. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates. EMBO J. 2024;43(22):5613–34. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lipogenesis plays a role in PINK1 stabilization, as suggested by identification of SREBF1/2 in a genome-wide siRNA screen.

    “A role of lipogenesis for PINK1 stabilization has been suggested before by the identification of the SREBF1/2 transcription factors in a genome-wide siRNA screen [15].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Ivatt RM, Sanchez-Martinez A, Godena VK, et al. Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy. Proc Natl Acad Sci U S A. 2014;111(23):8494–9. source

      In the RNAi-screen results section (page unavailable), the paper reports that SREBF1 knockdown reduced PINK1 stabilization after mitochondrial depolarization; the Discussion suggests a role for the SREBP lipogenesis pathway. It identifies SREBF2 as a close homolog of SREBF1, but does not identify SREBF2 as a screen hit or show that its knockdown affects PINK1 stabilization. The genome-wide screen used Drosophila RNAi, with subsequent validation in human cells, rather than a genome-wide siRNA screen. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The ATG9A p.S828L variant was identified in a female patient of Hispanic or Latino ethnicity who developed symptoms at 43 years of age, with onset symptoms including asymmetry, bradykinesia, gait difficulties, rigidity and resting tremor, and was unresponsive to anti-parkinson therapy.

    “The p.S828L variant was identified in a female patient with Hispanic or Latino ethnicity, who developed symptoms at 43 years of age. Onset symptoms included asymmetry, bradykinesia, gait difficulties, rigidity and resting tremor. This individual was unresponsive to anti-parkinson therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    ATG9A mRNA is regulated by miR-29a, miR-29b, and miR-29c, as confirmed by qRT-PCR.

    “we confirmed the regulation of ATG9A by miRNA-29 on RNA levels using qRT-PCR (Fig. 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    siRNA-mediated downregulation of ATG9A phenocopied the effects of miR-29 and significantly inhibited PRKN translocation.

    “siRNA-mediated downregulation of ATG9A phenocopied the effects of miR-29 and significantly inhibited PRKN translocation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ATG9A p.R631W variant was found in a white male diagnosed with PD at 43 years of age, responsive to L-DOPA, with initial symptoms of left hand tremor and gait difficulties.

    “The ATG9A p.R631W variant was found in a white male who was diagnosed with PD at 43 years of age and responsive to L-DOPA. Initial symptoms included left hand tremor and gait difficulties.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both ATG9A variants failed to restore PRKN translocation upon miR-29 expression and resulted in significantly reduced PRKN translocation compared to wildtype ATG9A.

    “When performing rescue experiments, both ATG9A variants failed to restore PRKN translocation upon miR-29 expression and resulted in significantly reduced PRKN translocation compared to ATG9A wildtype (Fig. 5C, D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither ATG9A siRNA nor miR-29a transfection affected mitochondrial membrane potential in untreated cells, and CCCP-induced depolarization remained intact in both conditions.

    “High-content imaging of TMRM-stained cells showed that neither ATG9A siRNA nor miR-29a transfection affected mitochondrial membrane potential in untreated cells. CCCP-induced depolarization also remained intact in both conditions (Fig. S4)”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Transfection of either member of miR-29 significantly reduced ATG9A protein levels compared to control siRNA to about 40%-70% depending on condition, in both absence and presence of CCCP.

    “Upon transfection of either member of miR-29, ATG9A protein levels were significantly reduced compared to control siRNA to about 40%–70% depending on the condition (Fig. 2D, E).”
    • Also stated in: § Identification of ATG9A as a miRNA-29 target gene · plain
      “Next, we verified that ATG9A protein was reduced by miR-29 in both the absence and presence of CCCP”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    84% of the 146 differentially expressed genes were downregulated upon miR-29a overexpression.

    “As expected upon overexpression of a miRNA, 84% of these were downregulated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-26a, miR-507, and the three members of the miR-29 family all significantly reduced PRKN translocation.

    “Likewise, miR-26a, miR-507, and the three members of the miR-29 family all significantly reduced PRKN translocation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ATG9A siRNA transfection reduced GFP-PRKN translocation by 50% at 2 h after CCCP and had a small but significant effect at 6 h.

    “Cells that underwent transfection with ATG9A siRNA showed a 50% reduction of GFP-PRKN translocation at 2 h and there was also a small but significant effect at 6 h after CCCP (Fig. 3A, B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    miR-29a had the strongest effect on PINK1-PRKN signaling, followed by miR-29c and miR-29b.

    “had the strongest effect with regards to PINK1-PRKN signaling, followed by miR-29c and miR-29b.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-29 overexpression and ATG9A knockdown did not affect mitochondrial membrane potential but resulted in reduced PINK1 protein stabilization upon CCCP treatment.

    “Both miR-29 overexpression and knockdown of ATG9A did not affect mitochondrial membrane potential but resulted in reduced PINK1 protein stabilization upon CCCP treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transfection with miR-29 or siRNA against ATG9A caused a reduction in PINK1 protein levels.

    “Transfection with miR-29 or siRNA against ATG9A both caused a reduction in PINK1 protein levels”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    siRNA-mediated silencing of ATG9A resulted in reduced PRKN translocation to damaged mitochondria and lower pS65-Ub levels.

    “siRNA-mediated silencing of ATG9A resulted in reduced PRKN translocation to damaged mitochondria and lower pS65-Ub levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All quantitative results are expressed as mean ± SD or SEM from at least three independent experiments.

    “All quantitative results are expressed as mean ± SD or SEM from at least three independent experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    miR-26a, miR-507, and the miR-29 family regulate the PINK1-PRKN pathway.

    “suggesting that they regulate the PINK1-PRKN pathway.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    PINK1 siRNA completely disrupted PINK1-PRKN-dependent mitophagy induction.

    “PINK1 siRNA was used as control and completely disrupted PINK1-PRKN-dependent mitophagy induction, as expected.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    PINK1 is a likely target of the inhibitory miRNAs identified in the screen.

    “As the most upstream regulator of this pathway, PINK1 is a likely target of the inhibitory miRNAs we identified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Several downregulated genes selected from RNAseq were confirmed by qRT-PCR, generally validating the RNAseq results.

    “Several downregulated genes with a broad range of fold changes (Fig. S2A) were selected and confirmed using quantitative reverse transcription PCR (qRT-PCR) of independently transfected cell cultures generally validating the RNAseq results (Fig. S2B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The average coverage per exon of ATG9A in whole genome sequencing was over 100X, with a minimum coverage of 51X.

    “The average coverage per exon of the ATG9A gene was over 100X, with a minimum coverage of 51X.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A has been shown to accumulate at sites with damaged mitochondria.

    “has been shown to accumulate at sites with damaged mitochondria [33]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Itakura E, Kishi-Itakura C, Koyama-Honda I, et al. Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy. J Cell Sci. 2012;125(Pt 6):1488–99. source

  • May combine two claims.

    Interpretationown data

    The ATG9A p.R631W and p.S828L variants act as loss-of-function variants.

    “This suggests that these variants act as loss-of-function variants”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The InBetween phenotype detected by the algorithm was confirmed PRKN translocation negative upon manual inspection.

    “A third, “InBetween” phenotype that was detected by the algorithm was confirmed PRKN translocation negative upon manual inspection.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ATG9A is a core autophagy protein and a member of the KEGG mitophagy pathway (ID 04137).

    “ATG9A is a core autophagy protein and a member of the KEGG mitophagy pathway (ID 04137).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites ID 04137

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductown data

    The mCherry-ATG9A expression range (pixel intensity 1500-4000) was independently validated to avoid ATG9A overexpression and remain within physiological range.

    “This expression range was independently validated to avoid ATG9A overexpression and to remain within the physiological range under identical experimental conditions (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The study validates miR-29 and its target gene ATG9A as novel regulators of PINK1-PRKN signaling.

    “Together, our study validates miR-29 and its target gene ATG9A as novel regulators of PINK1-PRKN signaling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The study provides proof of concept that functional cell biological screening approaches can uncover the genetic architecture of mitophagy and EOPD.

    “In conclusion, our study provides proof of concept and highlights the power of functional cell biological screening approaches to uncover the genetic architecture of mitophagy and EOPD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ATG9A is among SREBF1 target genes.

    “ATG9A was found among the SREBF1 target genes in ChIP-seq experiments [64]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Consortium EP. The ENCODE (ENCyclopedia of DNA elements) project. Science. 2004;306(5696):636–40. source
53 of 53

  • The paper relies on this without support.

    Mutations in PINK1 and PRKN explain only a small portion of EOPD cases.

    “because mutations in PINK1 and PRKN only explain a small portion of EOPD cases”

  • The paper relies on this without support.

    The PINK1 gene lacks a miR-29 binding site.

    “Together with the absence of a miR −29 binding site in the PINK1 gene”

  • The paper relies on this without support.

    The EOPD cohort of 208 individuals is representative of the EOPD population, such that variants found in it are relevant to EOPD generally.

    “We screened an EOPD cohort consisting of 208 individuals with an age at disease onset before the age of 50 years for mutations in the ATG9A gene.”

  • The paper relies on this without support.

    The cellular rescue assays in HeLa cells reflect the functional impact of ATG9A variants in human EOPD pathogenesis.

    “When performing rescue experiments, both ATG9A variants failed to restore PRKN translocation upon miR-29 expression and resulted in significantly reduced PRKN translocation compared to ATG9A wildtype (Fig. 5C, D).”

  • The paper relies on this without support.

    PINK1 is neither a predicted nor an experimentally validated target of miR-29.

    “While PINK1 is neither a predicted nor an experimentally validated target of miR-29, we observed changes in PINK1 protein levels.”

  • The paper relies on this without support.

    All members of the miR-29 family have the same seed sequence and targets.

    “All members have the same seed sequence and targets.”
6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Fiesel FC, Moussaud-Lamodiere EL, Ando M, et al. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci. 2014;127(Pt 16):3488–504.

Authors
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., Liu, Y., Wang, C., Kim, J., Wszolek, Z. K., Ross, O. A., Springer, W., & Fiesel, F. C.
Affiliations
  • Mayo Clinic in Florida (US)
  • Revvity (United States) (US)
  • Mayo Clinic (US)
Corresponding author
Fiesel, Fabienne C.
ORCID
Venue
Molecular Neurodegeneration Advances
Publisher
Springer Science and Business Media LLC
Published
2026-04-30
Volume
2
Issue
1
Pages
31-31
ISSN
3059-4944 (ISSN-L)
DOI
10.1186/s44477-026-00029-w
PMC
PMC13275600
OpenAlex
W7160067515
Semantic Scholar
f90f9ebd6b689ab41be877630613ec9e34e907a5
Cited by
0
References
65
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration Advances (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
Funders
  • Congressionally Directed Medical Research Programs (W81XWH-17-1-0249, W81XWH-17-1-0248)
  • National Institute of Neurological Disorders and Stroke (RF1NS085070)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
miR-29, ATG9A, mitophagy, early-onset Parkinson disease, miRNA target genes, loss-of-function mutations

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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