Defects in trafficking bridge Parkinson’s disease pathology and genetics
Abstract
Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms. Cell-extrinsic mechanisms, including inflammation and prion-like spreading, are proposed to have both protective and deleterious functions in Parkinson's disease.
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In PD or AD, only a minor subset of patients has a genetic mutation responsible for disease development.
“In PD or AD, only a minor subset of patients has a genetic mutation responsible for disease development (e.g., SNCA , PINK1 and PARK2 mutations in PD (Abeliovich and Gitler, 2016)(Pickrell and Youle, 2015), and APP, PSEN1, PSEN2 in AD (Van Cauwenberghe et al., 2016)).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Abeliovich and Gitler, 2016
Cites
Janeway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394 · see citing works
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in <i>PINK1</i>
Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., et al. (2004) · Science · doi:10.1126/science.1096284 · Cited by 3,481 · see citing works
Youle, R. J., & Narendra, D. P. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3028 · Cited by 3,273 · see citing works
The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
Pickrell, A. M., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.007 · Cited by 2,310 · see citing works
International Parkinson's Disease Genomics Consortium (IPDGC), Nalls, M. A., Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Investigator, T. A. J. D., (CHARGE), C. F. H. A. A. R. I. G. E., North American Brain Expression Consortium (NABEC), et al. (2014) · Nature Genetics · doi:10.1038/ng.3043 · Cited by 1,895 · see citing works
Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W.-H., Castillo, P. E., Shinsky, N., Verdugo, J. M. G., Armanini, M., Ryan, A., et al. (2000) · Neuron · doi:10.1016/s0896-6273(00)80886-7 · Cited by 1,722 · see citing works
Self-citationSelf-propagation of pathogenic protein aggregates in neurodegenerative diseases
Jucker, M., & Walker, L. C. (2013) · Nature · doi:10.1038/nature12481 · Cited by 1,663 · see citing works
Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J.-S., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-2751com · Cited by 1,265 · see citing works
α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
Bartels, T., Choi, J. G., & Selkoe, D. J. (2011) · Nature · doi:10.1038/nature10324 · Cited by 1,263 · see citing works
Kim, C., Ho, D.-H., Suk, J.-E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms2534 · Cited by 856 · see citing works
Mapping of a gene for Parkinson's disease to chromosome 4q21-q23
Polymeropoulos, M. H., Higgins, J. J., Golbe, L. I., Johnson, W. G., Ide, S. E., Di Iorio, G., Sanges, G., Stenroos, E. S., Pho, L. T., Schaffer, A. A., et al. (1996) · Science · doi:10.1126/science.274.5290.1197 · Cited by 788 · see citing works
Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia
Fellner, L., Irschick, R., Schanda, K., Reindl, M., Klimaschewski, L., Poewe, W., Wenning, G. K., & Stefanova, N. (2013) · Glia · doi:10.1002/glia.22437 · Cited by 697 · see citing works
Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons
Maday, S., Wallace, K. E., & Holzbaur, E. L. F. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201106120 · Cited by 681 · see citing works
Ashrafi, G., Schlehe, J. S., LaVoie, M. J., & Schwarz, T. L. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201401070 · Cited by 502 · see citing works
Synuclein activates microglia in a model of Parkinson's disease
Su, X., Maguire-Zeiss, K. A., Giuliano, R., Prifti, L., Venkatesh, K., & Federoff, H. J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.006 · Cited by 474 · see citing works
Pickrell, A. M., Huang, C.-H., Kennedy, S. R., Ordureau, A., Sideris, D. P., Hoekstra, J. G., Harper, J. W., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2015.06.034 · Cited by 327 · see citing works
Dettmer, U., Newman, A. J., Soldner, F., Luth, E. S., Kim, N. C., von Saucken, V. E., Sanderson, J. B., Jaenisch, R., Bartels, T., & Selkoe, D. (2015) · Nature Communications · doi:10.1038/ncomms8314 · Cited by 317 · see citing works
Tang, F.-L., Erion, J. R., Tian, Y., Liu, W., Yin, D.-M., Ye, J., Tang, B., Mei, L., & Xiong, W.-C. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0042-15.2015 · Cited by 269 · see citing works
Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes
Rannikko, E. H., Weber, S. S., & Kahle, P. J. (2015) · BMC Neuroscience · doi:10.1186/s12868-015-0192-0 · Cited by 185 · see citing works
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Hallmarks of neurodegenerative diseases
Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023) · Cell · doi:10.1016/j.cell.2022.12.032 · Cited by 1,789 · see citing works
Zou, W., Pu, T., Feng, W., Lu, M., Zheng, Y., Du, R., Xiao, M., & Hu, G. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0147-y · Cited by 396 · see citing works
di Domenico, A., Carola, G., Calatayud, C., Pons-Espinal, M., Muñoz, J. P., Richaud-Patin, Y., Fernandez-Carasa, I., Gut, M., Faella, A., Parameswaran, J., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.12.011 · Cited by 372 · see citing works
Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging
Plaza-Zabala, A., Sierra-Torre, V., & Sierra, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030598 · Cited by 323 · see citing works
Iannielli, A., Bido, S., Folladori, L., Segnali, A., Cancellieri, C., Maresca, A., Massimino, L., Rubio, A., Morabito, G., Caporali, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.089 · Cited by 239 · see citing works
The Association Between the Gut Microbiota and Parkinson’s Disease, a Meta-Analysis
Shen, T., Yue, Y., He, T., Huang, C., Qu, B., Lv, W., & Lai, H.-Y. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.636545 · Cited by 219 · see citing works
“The main neuropathological characteristics of PD are loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs) or Lewy neurites, which consist of the abnormal α-synuclein aggregates (Abeliovich and Gitler, 2016).”
BackgroundImpaired dopamine release in Parkinson’s disease
Cramb, K. M. L., Beccano-Kelly, D., Cragg, S. J., & Wade-Martins, R. (2023) · Brain · doi:10.1093/brain/awad064 · Cited by 207 · see citing works
A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology
Wie, J., Liu, Z., Song, H., Tropea, T. F., Yang, L., Wang, H., Liang, Y., Cang, C., Aranda, K., Lohmann, J., et al. (2021) · Nature · doi:10.1038/s41586-021-03185-z · Cited by 120 · see citing works
TET2 Regulates the Neuroinflammatory Response in Microglia
Carrillo-Jimenez, A., Deniz, Ö., Niklison-Chirou, M. V., Ruiz, R., Bezerra-Salomão, K., Stratoulias, V., Amouroux, R., Yip, P. K., Vilalta, A., Cheray, M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.013 · Cited by 104 · see citing works
The endocytic membrane trafficking pathway plays a major role in the risk of Parkinson's disease
Bandres‐Ciga, S., Saez‐Atienzar, S., Bonet‐Ponce, L., Billingsley, K., Vitale, D., Blauwendraat, C., Gibbs, J. R., Pihlstrøm, L., Gan‐Or, Z., The International Parkinson's Disease Genomics Consortium (IPDGC), et al. (2019) · Movement Disorders · doi:10.1002/mds.27614 · Cited by 90 · see citing works
The many ways tissue phagocytes respond to dying cells
Blander, J. M. (2017) · Immunological Reviews · doi:10.1111/imr.12537 · Cited by 84 · see citing works
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60 · see citing works
“Notably, heterozygous GBA carriers present the largest genetic risk factor for developing idiopathic Parkinson’s disease (PD) [58].”
BackgroundRecent progress in the role of autophagy in neurological diseases
Meng, T., Lin, S., Zhuang, H., Huang, H., He, Z., Hu, Y., Gong, Q., & Feng, D. (2019) · Cell Stress · doi:10.15698/cst2019.05.186 · Cited by 58 · see citing works
Choudhury, S. P., Bano, S., Sen, S., Suchal, K., Kumar, S., Nikolajeff, F., Dey, S. K., & Sharma, V. (2022) · npj Parkinson's Disease · doi:10.1038/s41531-022-00324-9 · Cited by 52 · see citing works
Wang, T., Peng, Q., Liu, B., Liu, Y., & Wang, Y. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00418 · Cited by 27 · see citing works
- Authors
- Abeliovich, A., & Gitler, A. D.
- Affiliations
- Columbia University (US)
- Stanford University (US)
- Corresponding author
- Abeliovich, Asa
- Gitler, Aaron D.
- ORCID
- Gitler, Aaron D.
- Venue
- Nature
- Published
- 2016-11
- Volume
- 539
- Issue
- 7628
- Pages
- 207-216
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2550736838
- Cited by
- 462
- References
- 19
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 39 · 2023: 40 · 2022: 55 · 2021: 61 · 2020: 79 · 2019: 53 · 2018: 53 · 2017: 34 · 2016: 2
- FWCI
- 6.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Parkinson's disease, dopaminergic neurons, axonal transport, lysosomal trafficking, protein aggregation, mitochondrial damage, neurodegeneration, inflammation, prion-like spreading, genetic risk factors, axon terminals
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Biological Transport, Endocytosis, Glucosylceramidase, Humans, Inflammation, Lysosomes, Models, Biological, Neurons, Parkinson Disease, Prions, Synaptic Vesicles, alpha-Synuclein, Molecular Targeted Therapy
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