Abstract
The discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies. Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein. Decreased elimination of α-synuclein can lead to its abnormal accumulation and aggregation, an important component of PD development. Further understanding of how decreased GCase activity increases risk for α-synuclein pathology can assist with the development of clinical biomarkers for early detection of synucleinopathies, as well as promote novel treatments tailored for people with a GBA1 mutation. Historically, α-synuclein has not been a reliable biomarker for PD. However, recent research on α-synuclein content within exosomes, which are small vesicles released by cells that carry specific cellular cargo, has yielded encouraging results. Moreover, decreased GCase activity has been shown to influence exosomal contents. Exosomes have emerged as a promising new avenue for the identification of novel biomarkers and therapeutic targets aimed at improving neuronal GCase function and limiting the development of synucleinopathies.
Original language | English (US) |
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Pages (from-to) | 35-46 |
Number of pages | 12 |
Journal | Molecular Genetics and Metabolism |
Volume | 129 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2020 |
Bibliographical note
Funding Information:Authors acknowledge funding from the Lysosomal Disease Network fellowship to RVK. The Lysosomal Disease Network ( U54NS065768 ) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Institutes of Health's National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS , NINDS , and NIDDK . This research was also supported by the NCATS , grant UL1TR002494 that offered a scholarship to PJ. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's NCATS.
Funding Information:
RVK have received grants from NIH, Pfizer Inc. and Sanofi-Genzyme outside of this work.PJT has received grants from NIH, Parkinson Study Group, Northwestern University, Biogen Inc., and Bristol-Myers Squibb.NJW has received grants from Sanofi-Genzyme and Takeda-Shire, personal fees from Sanofi-Genzyme, Takeda-Shire and Pfizer Inc., and non-financial support from Sanofi-Genzyme.Authors acknowledge funding from the Lysosomal Disease Network fellowship to RVK. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and National Institutes of Health's National Center for Advancing Translational Sciences (NCATS). This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. This research was also supported by the NCATS, grant UL1TR002494 that offered a scholarship to PJ. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's NCATS.
Funding Information:
PJ declare no conflict of interest. RVK have received grants from NIH , Pfizer Inc. and Sanofi-Genzyme outside of this work. JCC have received grants from NIH, Pfizer Inc. and Sanofi-Genzyme outside of this work. PJT has received grants from NIH, Parkinson Study Group , Northwestern University , Biogen Inc. , and Bristol-Myers Squibb . NJW has received grants from Sanofi-Genzyme and Takeda-Shire , personal fees from Sanofi-Genzyme, Takeda-Shire and Pfizer Inc., and non-financial support from Sanofi-Genzyme.
Publisher Copyright:
© 2019 Elsevier Inc.
Keywords
- Alpha-synuclein
- Biomarker
- Carriers
- Exosomes
- GBA1
- Gaucher disease