Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease
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...
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doaj-e9ed5cbfb2d74792a62fd261d07a66e62021-03-22T12:46:23ZengElsevierNeurobiology of Disease1095-953X2019-02-011227282Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's diseaseCaleb Pitcairn0Willayat Yousuf Wani1Joseph R. Mazzulli2The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USACorresponding author at: The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 12-369, Chicago, IL 60611, USA.; The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAThe 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.http://www.sciencedirect.com/science/article/pii/S0969996118300743Gaucher diseaseParkinson's diseaseAlpha-synucleinLewy bodiesLysosomal dysfunctioniPSC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Caleb Pitcairn Willayat Yousuf Wani Joseph R. Mazzulli |
spellingShingle |
Caleb Pitcairn Willayat Yousuf Wani Joseph R. Mazzulli Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease Neurobiology of Disease Gaucher disease Parkinson's disease Alpha-synuclein Lewy bodies Lysosomal dysfunction iPSC |
author_facet |
Caleb Pitcairn Willayat Yousuf Wani Joseph R. Mazzulli |
author_sort |
Caleb Pitcairn |
title |
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease |
title_short |
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease |
title_full |
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease |
title_fullStr |
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease |
title_full_unstemmed |
Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease |
title_sort |
dysregulation of the autophagic-lysosomal pathway in gaucher and parkinson's disease |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2019-02-01 |
description |
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. |
topic |
Gaucher disease Parkinson's disease Alpha-synuclein Lewy bodies Lysosomal dysfunction iPSC |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118300743 |
work_keys_str_mv |
AT calebpitcairn dysregulationoftheautophagiclysosomalpathwayingaucherandparkinsonsdisease AT willayatyousufwani dysregulationoftheautophagiclysosomalpathwayingaucherandparkinsonsdisease AT josephrmazzulli dysregulationoftheautophagiclysosomalpathwayingaucherandparkinsonsdisease |
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1724207958997336064 |