Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease
Open accessAbstract
The finding that mutations in the Gaucher's Disease (GD) gene GBA1 are a strong risk factor for Parkinson's Disease (PD) has allowed for unique insights into pathophysiology centered on disruption of the autophagic-lysosomal pathway. Protein aggregations in the form of Lewy bodies and the effects of canonical PD mutations that converge on the lysosomal degradation system suggest that neurodegeneration in PD is mediated by dysregulation of protein homeostasis. The well-characterized clinical and pathological relationship between PD and the lysosomal storage disorder GD emphasizes the importance of dysregulated protein metabolism in neurodegeneration, and one intriguing piece of this relationship is a shared phenotype of autophagic-lysosomal dysfunction in both diseases. Translational application of these findings may be accelerated by the use of midbrain dopamine neuronal models derived from induced pluripotent stem cells (iPSCs) that recapitulate several pathological features of GD and PD. In this review, we discuss evidence linking autophagic dysfunction to the pathophysiology of GD and GBA1-linked parkinsonism and focus more specifically on studies performed recently in iPSC-derived neurons.
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Autophagic/lysosomal dysfunction has a key role in the pathogenesis of PD, with many PD mutations associated with defects in these pathways.
“Autophagic/lysosomal dysfunction are also thought to have a key role in the pathogenesis of the disease, with many PD mutations being associated with defects in these pathways [262,263].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [262]
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Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
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- Authors
- Pitcairn, C., Wani, W. Y., & Mazzulli, J. R.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Mazzulli, Joseph R.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 122
- Pages
- 72-82
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC6138580
- OpenAlex
- W2790727932
- Cited by
- 75
- References
- 136
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 11 · 2023: 3 · 2022: 5 · 2021: 13 · 2020: 10 · 2019: 12 · 2018: 6
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS092823)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Gaucher disease, Parkinson's disease, GBA mutations, Lewy bodies, proteostasis, neurodegeneration, lysosomal storage disease, midbrain dopaminergic neurons, autophagy dysfunction
- MeSH terms
- Animals, Autophagy, Gaucher Disease, Humans, Lysosomes, Parkinson Disease
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