Lysosomal Dysfunction and α-Synuclein Aggregation in Parkinson's Disease: Diagnostic Links
ABSTRACT Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy–lysosomal system is i...
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| Published in: | Movement disorders Vol. 31; no. 6; pp. 791 - 801 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Blackwell Publishing Ltd
01.06.2016
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| Subjects: | |
| ISSN: | 0885-3185, 1531-8257, 1531-8257 |
| Online Access: | Get full text |
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| Summary: | ABSTRACT
Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy–lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α‐synuclein aggregation in PD. The degradation of α‐synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α‐synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read‐out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α‐synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society |
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| Bibliography: | ark:/67375/WNG-G3SZ807H-3 ArticleID:MDS26562 istex:537CA16BE5A9332BB80902063EAC4B69CF7CF13C GBA1 Relevant conflicts of interests/financial disclosures Genotyping in CSF of Parkinson's Disease Patients: A Confirmatory Study.” Research of Wilma D. J. van de Berg is funded by Stichting Parkinson Fonds, Internationale Stichting Alzheimer Onderzoek, Ligue Europeénne contre la Maladie d'Alzheimer, ZonMW Memorabel, Neuroscience Campus Amsterdam, and Roche Innovation Center. The authors declare no conflicts of interest. Wilma D. J. van de Berg reports the following disclosures: contract research and consultancy for Roche Pharma Research & Early Development. S.P.'s research is supported by a grant supported by Michael J. Fox Foundation for Parkinson's Disease for the project titled “Lysosomal Enzymes Activity and Funding agencies ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23 |
| ISSN: | 0885-3185 1531-8257 1531-8257 |
| DOI: | 10.1002/mds.26562 |