Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric α-Synuclein
Open accessAbstract
Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant alpha-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove alpha-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased alpha-syn oligomer accumulation in vitro, confirming the significance of autophagy in alpha-syn clearance. Finally, rotenone-induced alpha-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these findings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic alpha-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade alpha-syn aggregates.
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Mutant forms of synuclein and oligomers are dependent on the autophagy-lysosome pathway for their clearance.
“However, mutant forms of synuclein and oligomers are dependent on the autophagy–lysosome pathway for their clearance4–6.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [6]
Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.
“Several lines of evidence indicate a role for autophagy in the regulation of synuclein homeostasis5,6,15, suggesting that dysfunctional autophagic clearance may contribute to the development of synuclein inclusions.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [6]
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Lysosomal Degradation of α-Synuclein in Vivo
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Stavoe, A. K. H., & Holzbaur, E. L. F. (2019) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125242 · Cited by 328 · see citing works
“Analogously, knockdown of Beclin1 in M17 human neuroblastoma cells resulted in increased aggregations of α-synuclein oligomers (Yu et al. 2009).”
BackgroundLysosomal impairment in Parkinson's disease
Dehay, B., Martinez‐Vicente, M., Caldwell, G. A., Caldwell, K. A., Yue, Z., Cookson, M. R., Klein, C., Vila, M., & Bezard, E. (2013) · Movement Disorders · doi:10.1002/mds.25462 · Cited by 340 · see citing works
Self-citationFriedman, L. G., Lachenmayer, M. L., Wang, J., He, L., Poulose, S. M., Komatsu, M., Holstein, G. R., & Yue, Z. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5809-11.2012 · Cited by 303 · see citing works
“Several lines of evidence show that autophagy degrades -syn, particularly aggregate-prone forms of PD-linked mutants (Webb et al., 2003; Spencer et al., 2009; Yu et al., 2009).”
BackgroundAlpha-synuclein and Protein Degradation Systems: a Reciprocal Relationship
Xilouri, M., Brekk, O. R., & Stefanis, L. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8341-2 · Cited by 299 · see citing works
“3c) has now been reported in numerous studies [81, 122, 123].”
Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease
Moors, T. E., Hoozemans, J. J. M., Ingrassia, A. M. T., Beccari, T., Parnetti, L., Chartier‐Harlin, M., & van de Berg, W. D. J. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0154-3 · Cited by 279 · see citing works
“clearance of α-syn oligomers [72], as well as mutant [73] and post-translationally modified forms of α-syn, in cellular [74] and yeast [75] models of PD.”
BackgroundAutophagy and A lpha‐ S ynuclein: R elevance to P arkinson's D isease and R elated S ynucleopathies
Xilouri, M., Brekk, O. R., & Stefanis, L. (2016) · Movement Disorders · doi:10.1002/mds.26477 · Cited by 266 · see citing works
Protein degradation pathways in Parkinson’s disease: curse or blessing
Ebrahimi‐Fakhari, D., Wahlster, L., & McLean, P. J. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1004-6 · Cited by 255 · see citing works
“The resulting lipidated form of LC3, LC3-II, is attached to both sides of the autophagosome membrane but is removed from the outer membrane before fusion with lysosomes occurs.”
BackgroundResultInfluentialGenetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease
Gan-Or, Z., Dion, P. A., & Rouleau, G. A. (2015) · Autophagy · doi:10.1080/15548627.2015.1067364 · Cited by 260 · see citing works
Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases
Djajadikerta, A., Keshri, S., Tanasa, M. P., Prestil, R., Ryan, L., & Rubinsztein, D. C. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.035 · Cited by 238 · see citing works
“[93] Yu WH, Dorado B, Figueroa HY, Wang L, Planel E, Cookson MR, et al.”
BackgroundThe role of mTOR signaling in Alzheimer disease
Oddo, S. (2012) · Frontiers in Bioscience-Scholar · doi:10.2741/s310 · Cited by 235 · see citing works
Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
Chu, C. T. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.015 · Cited by 218 · see citing works
Boosting chaperone-mediated autophagy in vivo mitigates α-synuclein-induced neurodegeneration
Xilouri, M., Brekk, O. R., Landeck, N., Pitychoutis, P. M., Papasilekas, T., Papadopoulou-Daifoti, Z., Kirik, D., & Stefanis, L. (2013) · Brain · doi:10.1093/brain/awt131 · Cited by 207 · see citing works
“A protective role for the induction of macroautophagy against a-synuclein overexpression was described by Spencer et al. (2009) and Yu et al. (2009), whereas Cartier et al. (2012) showed that, in an a-synuclein transgenic mouse model, blocking UCHL1 function decreased a-synuclein levels, likely…”
BackgroundSiddiqui, A., Chinta, S. J., Mallajosyula, J. K., Rajagopolan, S., Hanson, I. M., Rane, A., Melov, S., & Andersen, J. K. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.024 · Cited by 182 · see citing works
“Loss of mitochondrial homeostasis is implicated in the pathogenesis of PD [41–43].”
BackgroundAutophagy and Neuronal Cell Death in Neurological DisordersPreprint
Nixon, R. A., & Yang, D.-S. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008839 · Cited by 179 · see citing works
“Macroautophagy stimulation by beclin 1 gene transfer, ATG overexpression, or rapamycin significantly ameliorates pathology in a-synuclein PD models (Spencer et al. 2009; Yu et al. 2009).”
BackgroundThe Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders
Vidoni, C., Follo, C., Savino, M., Melone, M. A. B., & Isidoro, C. (2016) · Medicinal Research Reviews · doi:10.1002/med.21394 · Cited by 164 · see citing works
α-Synuclein-Based Animal Models of Parkinson's Disease: Challenges and Opportunities in a New Era
Visanji, N. P., Brotchie, J. M., Kalia, L. V., Koprich, J. B., Tandon, A., Watts, J. C., & Lang, A. E. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.09.003 · Cited by 161 · see citing works
HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression
Song, J., Lu, J., Liu, L., Chen, L., Durairajan, S. S. K., Yue, Z., Zhang, H., & Li, M. (2013) · Autophagy · doi:10.4161/auto.26751 · Cited by 160 · see citing works
Dysfunction of Cellular Proteostasis in Parkinson’s Disease
Lehtonen, Š., Sonninen, T.-M., Wojciechowski, S., Goldsteins, G., & Koıstınaho, J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00457 · Cited by 145 · see citing works
“However, another study has revealed an increase of A53T α-SYN oligomers after pharmacological or molecular inhibition of macroautophagy (Yu et al., 2009).”
BackgroundDisruption of Protein Quality Control in Parkinson's DiseasePreprint
Cook, C. N., Stetler, C. T., & Petrucelli, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009423 · Cited by 145 · see citing works
“Mutant a-synuclein transgenic mice and human postmortem brain tissue from DLB patients also show an increase in beclin 1 and LC3-II levels, again suggesting that a-synuclein pathology is associated with an up-regulation in autophagic activity (Yu et al. 2009).”
BackgroundThe Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders
Velayati, A., Yu, W. H., & Sidransky, E. (2010) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-010-0102-x · Cited by 145 · see citing works
“In addition to the lysosome, the autophagic vacuole also has been determined to be a compartment requisite for αsynuclein clearance [69, 70] through the engulfment of the cytoplasmic or vesicular form of α-synuclein and its delivery to the lysosome for final degradation.”
BackgroundSelf-citationNeuronal autophagy and mitophagy in Parkinson's disease
Lizama, B. N., & Chu, C. T. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100972 · Cited by 149 · see citing works
Koch, J. C., Bitow, F., Haack, J., d’Hedouville, Z., Zhang, J.-N., Tönges, L., Michel, U., Oliveira, L. M. A., Jovin, T. M., Liman, J., et al. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.169 · Cited by 144 · see citing works
Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway
Klucken, J., Poehler, A.-M., Ebrahimi‐Fakhari, D., Schneider, J., Nuber, S., Rockenstein, E. M., Schlötzer-Schrehardt, U. M., Hyman, B. T., McLean, P. J., Masliah, E., et al. (2012) · Autophagy · doi:10.4161/auto.19371 · Cited by 135 · see citing works
Alteration of autophagosomal proteins (LC3, GABARAP and GATE-16) in Lewy body disease
Tanji, K., Mori, F., Kakita, A., Takahashi, H., & Wakabayashi, K. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.05.022 · Cited by 133 · see citing works
“reported that autophagy is induced in DLB, and its activity is insufficient to degrade abnormal aggregates (Yu et al., 2009).”
BackgroundDu, T., Wang, L., Duan, C., Lu, L., Zhang, J., Gao, G., Qiu, X., Wang, X., & Yang, H. (2015) · Autophagy · doi:10.1080/15548627.2015.1086055 · Cited by 129 · see citing works
“Conversely, the oligomerization of SNCA is induced by suppression of autophagic activity.(50) GBA-deficient cortical neurons and tissue had increased levels of monomeric and oligomeric SNCA species, which was reversed by treatment with C2 or rapamycin, likely through upregulation of the macroautophagic pathway (Figs.”
BackgroundSelf-citationDefective Autophagy in Parkinson’s Disease: Role of Oxidative Stress
Janda, E., Isidoro, C., Carresi, C., & Mollace, V. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8318-1 · Cited by 129 · see citing works
“In addition, these authors showed that prolonged exposure to nonlethal doses of rotenone actually strongly decreased autophagy levels in this cell system, indicating again that rotenone, rather than inducing autophagy, might interfere with autophagic machinery, possibly by reducing cell metabolism [119].”
BackgroundLoss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice
Sato, S., Uchihara, T., Fukuda, T., Noda, S., Kondo, H., Saiki, S., Komatsu, M., Uchiyama, Y., Tanaka, K., & Hattori, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-21325-w · Cited by 125 · see citing works
SNCA (α-synuclein)-induced toxicity in yeast cells is dependent on Sir2-mediated mitophagy
Sampaio‐Marques, B., Felgueiras, C., Silva, A., Rodrigues, M. L., Tenreiro, S., Franssens, V., Reichert, A. S., Outeiro, T. F., Winderickx, J., & Ludovico, P. (2012) · Autophagy · doi:10.4161/auto.21275 · Cited by 123 · see citing works
Members, E. W. E., Terron, A., Bal-Price, A., Paini, A., Monnet-Tschudi, F., Bennekou, S. H., Leist, M., & Schildknecht, S. (2018) · Archives of Toxicology · doi:10.1007/s00204-017-2133-4 · Cited by 124 · see citing works
“Moreover, an impairment of the UPS activity in the nigrostriatal system parallels mitochondrial dysfunction in PD patients (Ambrosi et al. 2014; Betarbet et al. 2005; McNaught and Jenner 2001a, b, 2003; Yu et al. 2009).”
BackgroundNeuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?
Wong, Y. C., Luk, K. C., Purtell, K., Burke, S., Stoessl, A. J., Trudeau, L., Yue, Z., Krainc, D., Oertel, W. H., Obeso, J. A., et al. (2019) · Movement Disorders · doi:10.1002/mds.27823 · Cited by 123 · see citing works
Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death
Mader, B. J., Pivtoraiko, V. N., Flippo, H. M., Klocke, B. J., Roth, K. A., Mangieri, L. R., & Shacka, J. J. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300145z · Cited by 118 · see citing works
Du, G., Liu, X., Chen, X., Song, M. L., Yan, Y., Jiao, R., & Wang, C.-C. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-03-0200 · Cited by 114 · see citing works
“Furthermore, as shown in Supplemental Figure S1 mutation of dHDAC6 leads to a more severe rough eye phenotype characterizing impaired ubiquitin proteasome system (UPS) (Belote and Fortier, 2002), suggesting that dHDAC6 may play a compensatory role in the impaired UPS.”
BackgroundmTOR Signaling in Parkinson’s Disease
Lan, A., Chen, J., Zhao, Y.-L., Chai, Z., & Hu, Y. (2016) · Neuromolecular medicine · doi:10.1007/s12017-016-8417-7 · Cited by 102 · see citing works
Role of Autophagy in Parkinson’s Disease
Cerri, S., & Blandini, F. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180226094351 · Cited by 107 · see citing works
Rotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease
Wu, F., Xu, H., Guan, J.-J., Hou, Y., Gu, J., Zhen, X., & Qin, Z. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.004 · Cited by 109 · see citing works
“There were increased levels of soluble, membrane-bound a-synuclein in the SNpc of PD patients (Vekrellis et al., 2011) and the LC3-II protein levels were also up-regulated in postmortem cortical tissue from patients of Dementia with Lewy-bodies (Yu et al., 2009).”
Ren, H., Zhai, W., Lu, X., & Wang, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.691881 · Cited by 101 · see citing works
Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology
Tyson, T., Steiner, J. A., & Brundin, P. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13449 · Cited by 102 · see citing works
Autophagic pathways in Parkinson disease and related disorders
Xilouri, M., & Stefanis, L. (2011) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399411001803 · Cited by 98 · see citing works
Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion
Tang, Q., Gao, P., Arzberger, T., Höllerhage, M., Herms, J. W., Höglinger, G. U., & Koeglsperger, T. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04138-0 · Cited by 99 · see citing works
Helley, M., Pinnell, J. R., Sportelli, C., & Tieu, K. (2017) · Frontiers in Genetics · doi:10.3389/fgene.2017.00177 · Cited by 95 · see citing works
“Impaired autophagy has been demonstrated in vivo using mice overexpressing wild-type α-synuclein (Ebrahimi-Fakhari et al., 2011) or A53T α-synuclein (Yu et al., 2009; Chen et al., 2015).”
BackgroundImport and Export of Misfolded α-Synuclein
Rodriguez, L., Marano, M. M., & Tandon, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00344 · Cited by 93 · see citing works
“Similarly, pharmacological or molecular inhibition of macroautophagy promotes the accumulation of A53T α-syn oligomers in neuroblastoma cells (Yu et al., 2009).”
BackgroundMitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD
Esteves, A. R., Arduíno, D. M., Silva, D. F., Oliveira, C. R., & Cardoso, S. M. (2011) · Parkinson s Disease · doi:10.4061/2011/693761 · Cited by 89 · see citing works
“In addition, rotenone-induced alphasyn aggregates were cleared following rapamycin stimulation of autophagy [246].”
Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model
Smith, W. W., Liu, Z. W., Liang, Y., Masuda, N., Swing, D. A., Jenkins, N. A., Copeland, N. G., Troncoso, J. C., Pletnikov, M. V., Dawson, T. M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq086 · Cited by 92 · see citing works
“The autophagy pathway is disrupted in patients and in animal models that involve accumulation of a-synuclein (28,42,43).”
BackgroundResultHou, Y.-S., Guan, J.-J., Xu, H.-D., Wu, F., Sheng, R., & Qin, Z.-H. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00285-15 · Cited by 87 · see citing works
“The increases in autophagy biomarkers and a number of autophagosomes have been found in PD animal models or postmortem brain tissues (46, 47).”
BackgroundPathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective
Yi, S., Wang, L., Wang, H., Ho, M. S.-C., & Zhang, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314753 · Cited by 90 · see citing works
Self-citationPhytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism
Limanaqi, F., Biagioni, F., Busceti, C. L., Ryskalin, L., Polzella, M., Frati, A., & Fornai, F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133274 · Cited by 86 · see citing works
“Conversely, exposure to autophagy inducers such as rapamycin, a gold-standard mTORC1 inhibitor, or overexpression of Beclin-1, boosts the clearance of α-syn [158,171,173].”
BackgroundAutophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
Arotçarena, M.-L., Teil, M., & Dehay, B. (2019) · Cells · doi:10.3390/cells8060565 · Cited by 85 · see citing works
“On the contrary, Beclin-1 or Atg5 silencing in A53T-α-syn expressing neuroblastoma M17 cells induced a significant increase of α-syn oligomers and aggregates [66].”
BackgroundMolecular Insights into Parkinson's Disease
Rochet, J., Hay, B. A., & Guo, M. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00011-4 · Cited by 83 · see citing works
Molecular machinery of macroautophagy and its deregulation in diseases
Wong, A. S. L., Cheung, Z. H., & Ip, N. Y. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.07.005 · Cited by 83 · see citing works
Schwarz, L., Goldbaum, O., Bergmann, M., Probst‐Cousin, S., & Richter‐Landsberg, C. (2012) · Journal of Molecular Neuroscience · doi:10.1007/s12031-012-9733-5 · Cited by 82 · see citing works
Review: Autophagy and neurodegeneration: survival at a cost?
Cherra, S. J., Dagda, R., & Chu, C. T. (2010) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01062.x · Cited by 99 · see citing works
α-synuclein impairs autophagosome maturation through abnormal actin stabilization
Sarkar, S., Olsen, A. L., Sygnecka, K., Lohr, K. M., & Feany, M. Β. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009359 · Cited by 79 · see citing works
“Brains from these rodent models also show induction of autophagic and lysosomal markers [68,70,72], further connecting α-synuclein with alterations in the autophagolysosomal system.”
BackgroundJayaraj, R. L., Beiram, R., Azimullah, S., Meeran, M. F. N., Ojha, S. K., Adem, A., & Jalal, F. Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207670 · Cited by 82 · see citing works
“Unlike MPP+ which required transporters to induce dopaminergic neuronal death, rotenone is highly lipophilic and thus eventually crosses blood-brain barrier effectively, Various studies have shown that oxidative stress and impairment of mitochondrial function results in accumulation of autophagy vacuoles and toxicity…”
BackgroundAutophagy in Aging and Alzheimer's Disease: Pathologic or Protective?
Barnett, A., & Brewer, G. J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101989 · Cited by 76 · see citing works
“A decrease in ATP levels by inhibition of complex I with rotenone initially increases the rate of autophagy in human neuroblastoma cells [45].”
The link between the SNCA gene and parkinsonism
Xu, W., Tan, L., & Yu, J. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.042 · Cited by 76 · see citing works
“studies (Choubey et al., 2011; Yu et al., 2009).”
Mechanisms of alpha-synuclein toxicity: An update and outlook
Brás, I. C., Xylaki, M., & Outeiro, T. F. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.005 · Cited by 73 · see citing works
Park, H.-J., Shin, J. Y., Kim, H., Oh, S. H., & Lee, P. H. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.01.028 · Cited by 73 · see citing works
“Thereafter, severalpathologic studies reportedan increase in theautophagosome marker LC3-II (Crews et al., 2010; Dehay et al., 2010; Higashi et al., 2011; Klucken et al., 2012; Tanji et al., 2011; Yu et al., 2009) and a decrease in the lysosomal marker LAMP1 (Chu et al.”
BackgroundWu, G., Wang, X., Feng, X., Zhang, A., Li, J., Gu, K., Huang, J. A., Pang, S., Dong, H., Gao, H., et al. (2011) · Brain Research · doi:10.1016/j.brainres.2011.04.013 · Cited by 75 · see citing works
“In transgenic mice overexpressing mutant α-synuclein, LC3-II was significantly increased in brains (Yu et al., 2009).”
Pivtoraiko, V. N., Harrington, A. J., Mader, B. J., Luker, A. M., Caldwell, G. A., Caldwell, K. A., Roth, K. A., & Shacka, J. J. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06838.x · Cited by 73 · see citing works
Genetically engineered mouse models of Parkinson's disease
Crabtree, D., & Zhang, J. (2011) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.07.019 · Cited by 71 · see citing works
“In fact, the autophagy lysosome pathway has been repeatedly shown to play a key role in -synuclein degradation [28,94,105,140,179], reviewed in [150], including the degradation of -synuclein aggregates [187,191].”
BackgroundTargeting the Autophagy/Lysosomal Degradation Pathway in Parkinsons Disease
Rivero-Ríos, P., Madero-Pérez, Fernández, B., & Hilfiker, S. (2016) · Current Neuropharmacology · doi:10.2174/1570159x13666151030103027 · Cited by 69 · see citing works
“Together, these data indicate that excess protein levels and/or distinct α-synuclein aggregates may interfere with autophagy at both early (induction) and late (clearance) steps, and this may further depend on additional factors such as metabolic activity [24].”
García‐García, A., Anandhan, A., Burns, M., Chen, H., Zhou, Y., & Franco, R. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft188 · Cited by 67 · see citing works
“An interesting study showed that chronic rotenone exposure impairs the ability of rapamycin to induce autophagy, suggesting that alterations in cellular metabolism by rotenone impair autophagic activity (Yu et al., 2009).”
BackgroundBurbidge, K. J., Rademacher, D. J., Mattick, J., Zack, S. R., Grillini, A., Bousset, L., Kwon, O., Kubicki, K., Simon, A., Melki, R., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1967615 · Cited by 63 · see citing works
Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function
Kim, D., Lim, H.-S., Kawasaki, I., Shim, Y., Vaikath, N. N., El‐Agnaf, O. M. A., Lee, H.-J., & Lee, S. (2016) · Autophagy · doi:10.1080/15548627.2016.1207014 · Cited by 65 · see citing works
Ottolini, D., Calí, T., Szabó, I., & Brini, M. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0201 · Cited by 63 · see citing works
Xu, Y., Cui, C., Sun, M., Zhu, Y., Chu, M., Shi, Y., Lin, S. L., Yang, X., & Shen, Y. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26010 · Cited by 65 · see citing works
“…is an increase in the autophagosome marker LC3-II, which is expressed on membranes of Lewy bodies and Lewy neurites, and the amount of LC3-II correlates with the number of autophagosomes, which has been used as an indicator of autophagy [Yu et al., 2009; Higashi et al., 2011; Tanji et al., 2011].”
BackgroundFan, R. Z., Guo, M. A., Luo, S., Cui, M., & Tieu, K. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0821-4 · Cited by 63 · see citing works
Serratos, I. N., Hernández‐Pérez, E., Campos, C., Aschner, M., & Santamarı́a, A. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02596-3 · Cited by 64 · see citing works
Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis
Erustes, A. G., Stefani, F. Y., Terashima, J. Y., Stilhano, R. S., Monteforte, P. T., Pereira, G. J. S., Han, S. W., Calgarotto, A. K., Hsu, Y., Ureshino, R. P., et al. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24092 · Cited by 64 · see citing works
“M17 or PC12 neuronal cells overexpressing WT a-synuclein or mutant proteins also appeared to have an increase in autophagy after treatment with rapamycin (Webb, Ravikumar, Atkins, Skepper, & Rubinsztein, 2003; Yu et al., 2009).”
BackgroundIt's a cell-eat-cell world: autophagy and phagocytosis.
Oczypok, E., Oury, T., & Chu, C. T. (2013) · American Journal of Pathology · doi:10.1016/j.ajpath.2012.12.017 · Cited by 65 · see citing works
Trifluoperazine rescues human dopaminergic cells from wild-type α-synuclein-induced toxicity
Höllerhage, M., Goebel, J. N., de Andrade, A., Hildebrandt, T., Dolga, A. M., Culmsee, C., Oertel, W. H., Hengerer, B., & Höglinger, G. U. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.01.027 · Cited by 62 · see citing works
Dunning, C. J. R., George, S., & Brundin, P. (2013) · Prion · doi:10.4161/pri.23806 · Cited by 63 · see citing works
Compagnoni, G. M., Kleiner, G., Samarani, M., Aureli, M., Faustini, G., Bellucci, A., Ronchi, D., Bordoni, A., Garbellini, M., Salani, S., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.09.007 · Cited by 62 · see citing works
“A possible involvement of this pathway has been described both in brains of patients with Lewy body disease and in mouse models (Klucken et al., 2012; Yu et al., 2009; Crews et al., 2010).”
BackgroundPhillipson, O. T. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.09.006 · Cited by 60 · see citing works
Synaptic dysfunction in genetic models of Parkinson's disease: A role for autophagy?
Plowey, E. D., & Chu, C. T. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.011 · Cited by 59 · see citing works
“Autophagy contributes to the degradation of α-synuclein (Webb et al., 2003; Yu et al., 2009), providing another avenue through which autophagy may impact synaptic function.”
Genetic analysis of the ATG7 gene promoter in sporadic Parkinson's disease
Chen, D., Pang, S., Feng, X., Huang, W., Hawley, R. G., & Yan, B. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2012.12.039 · Cited by 59 · see citing works
Lysosomal function in macromolecular homeostasis and bioenergetics in Parkinson's disease
Schneider, L. E., & Zhang, J. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-14 · Cited by 57 · see citing works
Deregulation of autophagy and vesicle trafficking in Parkinson’s disease
Sheehan, P., & Yue, Z. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.013 · Cited by 57 · see citing works
Li, D., Mastaglia, F. L., Fletcher, S., & Wilton, S. D. (2020) · Medicinal Research Reviews · doi:10.1002/med.21718 · Cited by 57 · see citing works
“Normal monomeric α‐synuclein is usually degraded by chaperone‐mediated autophagy, while macroautophagy has been implicated in the clearance of α‐synuclein oligomers.(59) The burden of toxic α‐synuclein aggregates, may compromise the macroautophagy pathway through interfering with autophagosome formation or clearance.”
BackgroundWan, T., Weir, E. J., Johnson, M., Korolchuk, V. I., & Saretzki, G. C. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101953 · Cited by 52 · see citing works
“Aggregation-prone substrates such as oligomeric α-syn resistant to both the UPS and the CMA can be degraded by macroautophagy (Yu et al., 2009).”
BackgroundGenetic causes of Parkinson's disease and their links to autophagy regulation
Pan, P., & Yue, Z. (2013) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(13)70037-3 · Cited by 52 · see citing works
“Knocking down a-synuclein disrupts autophagy and results in accumulated a-synuclein oligomer [8].”
BackgroundRole of Autophagy Pathway in Parkinson’s Disease and Related Genetic Neurological Disorders
Themistokleous, C., Bagnoli, E., Parulekar, R., & Muqit, M. M. K. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168144 · Cited by 49 · see citing works
A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease
Chen, D., Zhu, C., Wang, X., Feng, X., Pang, S., Huang, W., Hawley, R. G., & Yan, B. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.01.044 · Cited by 46 · see citing works
Protein Quality Control Pathways at the Crossroad of Synucleinopathies
de Mattos, E. P., Wentink, A. S., Nussbaum-Krammer, C. I., Hansen, C., Bergink, S., Melki, R., & Kampinga, H. H. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-191790 · Cited by 45 · see citing works
“Data supporting a role for macroautophagy in the degradation of monomeric and pre-fibrillar Syn assemblies come mainly from studies detecting -Syn buildup upon exposure of cell lines overexpressing either WT or mutant -Syn variants to the inhibitor of autophagosome formation 3methyladenine [93, 95, 97, 131].”
BackgroundGlucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease
Parkkinen, L., Neumann, J., O’Sullivan, S. S., Holton, J. L., Révész, T., Hardy, J., & Lees, A. J. (2011) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2011.04.015 · Cited by 45 · see citing works
Martínez‐Vicente, M., & Vila, M. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.03.005 · Cited by 44 · see citing works
Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association
Teixeira, M., Sheta, R., Idi, W., & Oueslati, A. (2021) · Biomolecules · doi:10.3390/biom11091333 · Cited by 43 · see citing works
“Under general lysosomal inhibition, experiments performed in vitro and in vivo, shed light on the presence of specific co-localization between LAMP2A, LC3-II, and α-syn aggregates, confirming a strong involvement of the macroautophagy pathway in the degradation of the pathogenic forms of α-syn [111,112].”
BackgroundZheng, H.-F., Yang, Y., Hu, L., Wang, M., Wang, F., Cao, L.-D., Li, D., Mao, C., Xiong, K., Wang, J.-D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070472 · Cited by 43 · see citing works
“Neuronal autophagy is essential for protein homeostasis, and autophagy dysfunction increases the accumulation of potentially pathogenic a-SYN oligomers [34].”
BackgroundParkinson's disease, proteins, and prions: Milestones
Olanow, C. W., & McNaught, K. S. P. (2011) · Movement Disorders · doi:10.1002/mds.23767 · Cited by 42 · see citing works
“For example, impairment of autophagy by RNA interference increased a-synuclein oligomer accumulation and induced degeneration in vitro, whereas rotenone-induced a-synuclein aggregates were cleared following stimulation of autophagy by rapamycin.(174) Glucocorticoids such as dexamethasone can stimulate UPS-mediated pro…”
BackgroundGonzález‐Casacuberta, I., Juárez‐Flores, D. L., Morén, C., & Garrabou, G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00894 · Cited by 43 · see citing works
“…an upregulation of macroautophagy following an overwhelmed chaperone-mediated autophagy (CMA) system as a result of overexpression of misfolded aggregates of α-synuclein has been shown in mice and in vitro PD model systems (Spencer et al., 2009; Yu et al., 2009; Ebrahimi-Fakhari et al., 2011).”
Background
- Authors
- Yu, W. H., Dorado, B., Figueroa, H. Y., Wang, L., Planel, E., Cookson, M. R., Clark, L. N., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Columbia University (US)
- Centre hospitalier de l'Université Laval (CA)
- National Institutes of Health (US)
- Corresponding author
- Duff, Karen E.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 175
- Issue
- 2
- Pages
- 736-747
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2716969
- OpenAlex
- W1983315832
- Cited by
- 155
- References
- 72
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 10 · 2023: 6 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 7 · 2013: 14 · 2012: 19
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Parkinson's Disease Foundation
- National Institutes of Health
- National Institute on Aging (Z01-AG000948)
- National Institute of Neurological Disorders and Stroke (NS050487)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- macroautophagy, alpha-synuclein, oligomeric alpha-synuclein, Parkinson's disease, dementia with Lewy bodies, synucleinopathies, LC3-II, Beclin-1, aging, cellular metabolism, rapamycin, rotenone, protein aggregate clearance, autophagy induction, proteostasis
- MeSH terms
- Aged, Aged, 80 and over, Aging, Animals, Autophagy, Brain, Female, Humans, Male, Mice, Transgenic, Parkinson Disease, Mice, alpha-Synuclein
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