Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration

In the paper

“TLR4-NF-κB signaling was previously shown to induce selective autophagy after pathogen invasion52–54.”

What the sources say

• Partly supported

  The ‘TLRs Induce Autophagy in Murine’ section reports that TLR4 ligands induced autophagosome formation in macrophages. The Discussion identifies MyD88, Trif and Beclin 1 in the proposed mechanism; although it mentions TLR-mediated NF-κB activation, it does not show that NF-κB induces the autophagy. The experiments also do not establish selective autophagy after pathogen invasion. (LLM, conf=0.88)

  cites [52] Shi, C. S. & Kehrl, J. H. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J. Biol. Chem. 283, 33175–33182 (2008). sourceExperimental — accuracy not yet measured
• Disputed

  In Results, under “Cytosolic DNA Sensing Mediates Targeting of M. tuberculosis to Autophagosomes” (page unavailable), the paper reports that autophagy targeting remained normal in macrophages deficient in TLR signaling. It instead identifies cytosolic DNA sensing through STING as necessary for selective targeting of M. tuberculosis; it does not show induction by TLR4–NF-κB signaling. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  cites [53] Watson, R. O., Manzanillo, P. S. & Cox, J. S. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803–815 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results show that LPS induces autophagy through TLR4, and the Discussion identifies a TRIF-dependent pathway involving RIP1 and p38 MAPK. The paper also reports colocalization of mycobacterial phagosomes with autophagosomes, but it does not establish NF-κB as the mediator or characterize the response as selective autophagy after pathogen invasion. (LLM, conf=0.88)

  cites [54] Xu, Y. et al. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27, 135–144 (2007). sourceExperimental — accuracy not yet measured

In the paper

“A number of studies demonstrated that α-synuclein can enter the cells or penetrate cytoplasmic membrane through endocytosis-independent process61–63.”

What the sources say

• Supported

  The Abstract reports that α-synuclein enters cells rapidly and that endocytosis inhibitors did not significantly affect its membrane translocation. The Discussion concludes that uptake occurs by a route distinct from normal endocytosis. Page numbers are not provided in our copy's passages. (LLM, conf=0.91)

  cites [61] Ahn, K. J., Paik, S. R., Chung, K. C. & Kim, J. Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein. J. Neurochem. 97, 265–279 (2006). source
• ?Not checked — no full text of the sourcecites [62] Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008). source
• Disputed

  The Discussion describes extracellular monomeric α-synuclein entering microglia via GM1-mediated endocytosis. It says this uptake is independent of clathrin, caveolae and dynamin, but lipid raft-dependent; independence from those pathways is not independence from endocytosis. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [63] Park, J. Y. et al. On the mechanism of internalization of alpha-synuclein into microglia: roles of ganglioside GM1 and lipid raft. J. Neurochem. 110, 400–411 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Atg7 encodes an E1-like enzyme essential in the ubiquitin-like conjugation systems required for autophagy, and Atg14 encodes a positive regulator of VPS34 (refs. 38,39).”

What the sources say

• Supported

  The Introduction describes Atg7p as an E1-like enzyme that activates components of both ubiquitin-like conjugation systems. The Results state that Atg7 is essential for those systems and autophagosome formation in mice. This Atg7 paper supports the Atg7 clause; the separately cited Atg14 clause is not attributed to it. (LLM, conf=0.92)

  cites [38] Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005). source
• Supported

  This source addresses the Atg14 clause of the sentence, rather than the Atg7 clause. The Introduction identifies Atg14L as a subunit of the autophagy-specific Vps34 PI3-kinase complex, and the Results and discussion conclude that Atg14L recruits that complex to the ER for autophagy. This supports describing Atg14 as a positive regulator of Vps34 in this context. (LLM, conf=0.86)

  cites [39] Matsunaga, K. et al. Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J. Cell Biol. 190, 511–521 (2010). source

In the paper

“Aggregated α-synuclein is a major component in intraneuronal inclusions known as Lewy bodies (LB) associated with neurodegenerative diseases, such as Parkinson’s disease (PD) and dementia with Lewy body (DLB)5,6.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Baba, M. et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884 (1998).
• Partly supported

  The Introduction describes α-synuclein in the form of Lewy body–related pathology in Parkinson’s disease and discusses that pathology in dementia with Lewy bodies. It does not specify that Lewy bodies are intraneuronal inclusions or that aggregated α-synuclein is a major component of them. (LLM, conf=0.82)

  cites [6] Toledo, J. B. et al. Pathological alpha-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology. Acta Neuropathol. 131, 393–409 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Previous reports showed α-synuclein can trigger TLR4 or TLR2 activation in cultured glia, which leads to an increase in inflammatory gene transcription19,40,41.”

What the sources say

• Supported

  The Results section ('Role of Tlr2 in α-synuclein-induced microglia activation') reports that α-synuclein released from cells induced inflammatory cytokine and chemokine genes in cultured microglia through TLR2. This supports the TLR2 alternative in the citing sentence; the paper does not support TLR4 activation by the α-synuclein preparation it tested. (LLM, conf=0.91)

  cites [19] Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). source
• Partly supported

  The Results (page unavailable) show that α-synuclein treatment caused TLR4-dependent NF-κB nuclear translocation and increased inflammatory cytokine release in cultured murine glia. The paper measured cytokine release, not an increase in inflammatory gene transcription; its experiments address TLR4 rather than TLR2. (LLM, conf=0.84)

  cites [40] Fellner, L. et al. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports that α-synuclein increased inflammatory-gene mRNA in cultured astrocytes, with no significant induction in Tlr4−/− astrocytes. This directly supports the TLR4 alternative in the citing sentence; the paper also discusses prior reports of TLR2-mediated microglial activation, but does not establish TLR2-dependent transcription in its own experiments. (LLM, conf=0.93)

  cites [41] Rannikko, E. H., Weber, S. S. & Kahle, P. J. Exogenous alpha-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neurosci. 16, 57 (2015). source

In the paper

“p62/SQSTM1, an autophagy receptor34”

• Also stated in: § p62 mediates sequestration and degradation of α-synuclein · boosted

  “p62 is known to recognize and interact with ubiquitinated cargo to initiate selective autophagy34.”

What the sources say

• Supported

  The LIR–LC3/GABARAP Interaction section explicitly identifies p62/SQSTM1 as a cargo receptor for selective autophagy of ubiquitinated substrates. The Conclusions section also describes how p62 binds ubiquitin on substrates and links them to the forming autophagosome. (LLM, conf=0.94)

  cites [34] Lamark, T., Kirkin, V., Dikic, I. & Johansen, T. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8, 1986–1990 (2009). source

In the paper

“TLR4-LPS binding induces endocytosis of the TLR4-LPS complex and subsequent expression of interferon-beta 1 (Ifnb1) through activation of interferon regulatory factor 3 (IRF3)43,44.”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Sakaguchi, S. et al. Essential role of IRF-3 in lipopolysaccharide-induced interferon-beta gene expression and endotoxin shock. Biochem. Bioph. Res. Commun. 306, 860–866 (2003). source
• Supported

  The Introduction (page unavailable) describes TLR4 encountering LPS, then entering endosomes, where TRAM–TRIF signaling activates IRF3 to regulate type I interferon expression. The Discussion (page unavailable) also describes transport of both TLR4 and LPS to endosomes. Together, these passages support the cited sequence leading to interferon-beta expression. (LLM, conf=0.88)

  cites [44] Zanoni, I. et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868–880 (2011). source

In the paper

“Torin1, an inhibitor of mTOR that stimulates autophagy37”

What the sources say

• Partly supported

  The Abstract identifies Torin1 as an mTOR inhibitor, and the Introduction says mTOR regulates autophagy. Our copy does not state that Torin1 stimulates autophagy; the autophagy claim is therefore unsupported by this source. (LLM, conf=0.86)

  cites [37] Liu, Q. S. et al. Discovery of 1-(4-(4-Propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective mammalian target of rapamycin (mTOR) inhibitor for the treatment of cancer. J. Med. Chem. 53, 7146–7155 (2010). sourceExperimental — accuracy not yet measured

In the paper

“Previous studies suggest that α-synuclein is degraded by macroautophagy, chaperone-mediated autophagy, and the proteasome20–23.”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004). source
• Supported

  The paper’s introductory passage explicitly says that proteasomes, macroautophagy, and chaperone-mediated autophagy have all been implicated in α-synuclein degradation. Its results section also reports contributions from proteasomes and macroautophagy to basal degradation. The claim appropriately frames these pathways as suggestions from previous studies. (LLM, conf=0.95)

  cites [21] Tofaris, G. K. et al. Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway. Proc. Natl Acad. Sci. USA 108, 17004–17009 (2011). source
• Supported

  The opening passage reports studies suggesting proteasomal degradation, while the Discussion reports macroautophagic clearance and the neuronal-cell results report degradation by CMA. The paper also says its own proteasomal-inhibition experiments found no significant effect, so the proteasome portion is supported as a suggestion from previous studies, not as this study’s finding. (LLM, conf=0.87)

  cites [22] Vogiatzi, T., Xilouri, M., Vekrellis, K. & Stefanis, L. Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542–23556 (2008). source
• Partly supported

  The Discussion reports that α-synuclein is degraded by the proteasome and autophagy in inducible PC12 cells. The paper describes autophagy through the formation of autophagosomes, consistent with macroautophagy, but our copy does not address chaperone-mediated autophagy; a search for that term found no supporting passage. (LLM, conf=0.87)

  cites [23] Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. alpha-synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003). sourceExperimental — accuracy not yet measured

In the paper

“p62 has a role in the clearance of intra-cytosolic Shigella and Listeria55.”

What the sources say

• Partly supported

  The Discussion says p62 targets the Listeria ActA mutant to an autophagy pathway, supporting a role in its clearance. The section on p62 and NDP52 recruitment specifies that wild-type Listeria avoids p62 recognition, so the claim is too broad without the ActA-mutant qualification. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites [55] Mostowy, S. et al. p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. J. Biol. Chem. 286, 26987–26995 (2011). sourceExperimental — accuracy not yet measured

In the paper

“A number of studies demonstrated that α-synuclein can enter the cells or penetrate cytoplasmic membrane through endocytosis-independent process61–63.”

What the sources say

• Supported

  The Discussion reports that α-synuclein entered cells despite treatment with endocytosis inhibitors and concludes that uptake occurs by a route distinct from normal endocytosis. This supports the citing sentence’s description of an endocytosis-independent process; the supplied passages do not give page numbers. (LLM, conf=0.92)

  cites [61] Ahn, K. J., Paik, S. R., Chung, K. C. & Kim, J. Amino acid sequence motifs and mechanistic features of the membrane translocation of alpha-synuclein. J. Neurochem. 97, 265–279 (2006). source
• ?Not checked — no full text of the sourcecites [62] Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008). source
• Partly supported

  The Discussion reports that high-dose α-synuclein uptake can be temperature-independent and that monomeric uptake into microglia is independent of clathrin, caveolae and dynamin. But it describes the studied route as lipid-raft-dependent endocytosis, not as independent of endocytosis altogether. No page number is available in our copy. (LLM, conf=0.85)

  cites [63] Park, J. Y. et al. On the mechanism of internalization of alpha-synuclein into microglia: roles of ganglioside GM1 and lipid raft. J. Neurochem. 110, 400–411 (2009). sourceExperimental — accuracy not yet measured

In the paper

“TLR2 also plays a role in neurons in response to α-synuclein in addition to microglia19,57,58.”

What the sources say

• Supported

  The Results section, “Role of Tlr2 in α-synuclein-induced microglia activation,” reports reduced signaling in Tlr2-deficient microglia and concludes that TLR2 mediates their response to α-synuclein. The in vivo Results section likewise reports lower microglial activation in Tlr2-deficient mice. (LLM, conf=0.94)

  cites [19] Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). source
• Supported

  The Introduction states that α-synuclein can activate TLR2 on microglia and promote inflammatory cytokine production. The Discussion likewise reports that oligomeric and fibrillar α-synuclein activate microglial TLR2 in tissue-culture experiments. (LLM, conf=0.93)

  cites [57] Dzamko, N. et al. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 133, 303–319 (2017). source
• Supported

  The Discussion reports that α-synuclein oligomers released from neurons activate TLR2 in microglia and induce proinflammatory responses. Although it describes this as a previous finding, the paper reports and relies on it when discussing microglia-based mechanisms. (LLM, conf=0.92)

  cites [58] Kim, C. et al. Antagonizing neuronal Toll-like receptor 2 prevents synucleinopathy by activating autophagy. Cell Rep. 13, 771–782 (2015). source

In the paper

“p62 has a role in the clearance of intra-cytosolic Shigella and Listeria55.”

What the sources say

• Supported

  The Results report that p62 and NDP52 act interdependently to target intracytosolic Shigella toward autophagy. The Discussion links this pathway to bacterial clearance, supporting the stated role for p62. (LLM, conf=0.91)

  cites [55] Mostowy, S. et al. p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. J. Biol. Chem. 286, 26987–26995 (2011). source

In the paper

“TLR2 also plays a role in neurons in response to α-synuclein in addition to microglia19,57,58.”

What the sources say

• Partly supported

  The Results section on TLR2 upregulation reports TLR2 labeling in pyramidal neurons, but the α-synuclein-related increase it describes is in microglia. The in vivo Results show that α-synuclein expressed by neurons activates microglia through TLR2; they do not establish that TLR2 mediates a neuronal response to α-synuclein. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  cites [19] Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report neuronal TLR2 expression and show that activating neuronal TLR2 increases α-synuclein protein. They do not show that neurons activate TLR2 in response to α-synuclein; the experiments activated TLR2 with an agonist, so the direction implied by “in response to” is not established. (LLM, conf=0.83)

  cites [57] Dzamko, N. et al. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 133, 303–319 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports that TLR2 is expressed in neurons and that its activation increases α-synuclein accumulation and toxicity in human neural precursor cells. TLR2 knockdown reduced those effects, supporting a neuronal role alongside the microglial role discussed in the paper. (LLM, conf=0.92)

  cites [58] Kim, C. et al. Antagonizing neuronal Toll-like receptor 2 prevents synucleinopathy by activating autophagy. Cell Rep. 13, 771–782 (2015). source

In the paper

“emerging human genomic studies suggest the autophagy–lysosome system as a converging pathogenic pathway of PD64”

What the sources say

• Supported

  The paper states that its genetic findings indicate a key role for autophagy and lysosomal biology in PD risk (Abstract). It also reports enrichment of PD-associated signals among autophagy and lysosomal genes, supporting the citing sentence’s hedged description of a converging pathway. (LLM, conf=0.92)

  cites [64] Chang, D. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516 (2017). source

In the paper

“many PD-related genes such as PINK1, PARKIN, GBA, and LRRK2, were shown to play a role in autophagy-related pathways in glial cells65.”

What the sources say

• Partly supported

  The Introduction and the sections on PARK2/PINK1, GBA, and LRRK2 link these PD-related genes to autophagy or lysosomal pathways. The passages do not establish that these roles were shown specifically in glial cells, so the cell-type qualifier is unsupported. (LLM, conf=0.88)

  cites [65] Gan-Or, Z., Dion, P. A. & Rouleau, G. A. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11, 1443–1457 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Thus, we concluded that microglia engulf extracellular α-syn protein, which is sequestered by autophagosomes and degraded by the autophagy–lysosome pathway.”

• Also stated in: § Abstract · plain

  “which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy).”

In the paper

“total LC3-II levels changed little after hα-Syn treatment (Supplementary Fig. 4i), suggesting no significant alteration of overall autophagy.”

• Also stated in: § p62 mediates sequestration and degradation of α-synuclein · hedged

  “other autophagy receptors such as Ndp52, Optineurin, and Nbr1 were not altered (Supplementary Fig. 4i), suggesting that hα-Syn selectively induces p62 expression without affecting other autophagy receptors.”

In the paper

“We observed that hα-Syn treatment caused an increase in p62 protein up to 9 h (Fig. 3a).”

• Also stated in: § p62 mediates sequestration and degradation of α-synuclein · plain

  “p62 mRNA levels peaked at 3 h, declined at 6 h, and returned to baseline at 9 h post treatment (Fig. 3b)”

In the paper

“Actinomycin D, a blocker of mRNA translation, inhibited p62 induction when added before hα-Syn treatment (Supplementary Fig. 4g) and suppressed the formation of hα-Syn/ubiquitin-positive puncta (Supplementary fig. 4h).”

In the paper

“Neither cytochalasin D, a blocker of actin polymerization necessary for phagocytosis, nor Dynasore, a GTPase inhibitor that suppresses both clathrin-dependent and independent endocytosis, inhibited the uptake of hα-Syn protein but rather it increased the uptake (Supplementary Figs. 4b, 5a, 5b).”

In the paper

“only ML-120B significantly suppressed p62 induction and reduced the number of hα-Syn/ubiquitin-positive puncta after hα-Syn treatment (Fig. 5b, c)”

In the paper

“Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration.”

In the paper

“LPS, but not hα-Syn, induced Ifnb1 expression (Fig. 4h) and increased levels of p-IFR3 (S396), a marker of IRF3 activation (Fig. 4i), indicating the absence of IRF3 signaling in hα-Syn-treated microglia.”

In the paper

“Similar to Tlr4-KO microglia, TAK-242-treated cells showed impaired p62 induction (Fig. 4d) as well as a reduction in the number of hα-Syn/ubiquitin-positive puncta following hα-Syn treatment (Fig. 4e).”

In the paper

“TAK-242, an inhibitor of TLR4 signaling by selectively binding to Cys747 of TLR4 cytoplasmic tail that disrupts its interaction with adaptor molecules TIRAP and TRAM42”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Matsunaga, N., Tsuchimori, N., Matsumoto, T. & Ii, M. TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol. Pharm. 79, 34–41 (2011). source

In the paper

“The above observations suggest that the hα-Syn-TLR4 interaction stimulates p62 expression without causing TLR4 receptor endocytosis distinctively from LPS-TLR4 signaling.”

In the paper

“Recent evidence demonstrates a strong selectivity for autophagy28.”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014). source

In the paper

“Thus, our results uncover a microglia-specific α-synuclein degradation pathway termed synucleinphagy that regulates α-synuclein homeostasis in the CNS.”

In the paper

“Previous evidence suggested “prion-like” cell-to-cell transmission of α-synuclein9,10.”

What the sources say

• ?Not checked — no full text of the sourcecites [9] Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14, 504–506 (2008). source
• ?Not checked — no full text of the sourcecites [10] Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008). source

In the paper

“Autophagy is a bulk degradation pathway responsible for the clearance of protein aggregates and damaged cellular organelles26,27.”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011). source
• ?Not checked — no full text of the sourcecites [27] Yamamoto, A. & Yue, Z. Autophagy and its normal and pathogenic states in the brain. Annu. Rev. Neurosci. 37, 55–78 (2014). source

In the paper

“SAR405, an inhibitor of VPS34, which is a class III phosphatidylinositol 3-kinase required for autophagosome membrane synthesis36”

What the sources say

• ?Not checked — no full text of the sourcecites [36] Ronan, B. et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 10, 1013 (2014). source

In the paper

“Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway.”

In the paper

“Increased α-synuclein level due to the multiplication of SNCA alleles is causal to PD7,8.”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Chartier-Harlin, M. C. et al. alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1167–1169 (2004). source
• ?Not checked — no full text of the sourcecites [8] Singleton, A. B. et al. alpha-synuclein locus triplication causes Parkinson’s disease. Science 302, 841–841 (2003). source

In the paper

“We document that ingested α-synuclein in microglia is sequestered by autophagosomes for degradation, which is mediated by TLR4-NF-κB signaling through upregulation of the autophagy receptor, p62/SQSTM1.”

In the paper

“supporting that oligomeric p62 directly binds and recruits hα-Syn into autophagosomes.”

In the paper

“likely due to lack of the TLR4-NF-κB pathway.”

In the paper

“Application of LPS, Pam3CSK4, and recombinant Flagellin peptides selectively increased NF-κB activity in TLR4 complex, TLR2 and TLR2 combinations, and TLR5, respectively (Supplementary Fig. 6).”

In the paper

“Application of LPS, Pam3CSK4, and recombinant Flagellin peptides selectively increased NF-κB activity in TLR4 complex, TLR2 and TLR2 combinations, and TLR5, respectively (Supplementary Fig. 6).”

In the paper

“Data are representative of at least three independent experiments unless indicated.”

In the paper

“These parameters yielded a coefficient of error <10% throughout the analysis.”

In the paper

“our study supports a model that a portion of extracellular α-synuclein interacts with TLR4 (or TLR2), which then triggers NF-κB signaling, while a majority of α-synuclein penetrates cytoplasmic membrane or enters microglia through TLR4 endocytosis-independent manner.”

In the paper

“Data are representative of at least three independent experiments.”