Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle. (February 2015)

• Record Type: Journal Article
• Authors: Sardi, S. Pablo; Cheng, Seng H.; Shihabuddin, Lamya S.
• Is Part Of: Progress in neurobiology. Volume 125(2015:Feb.)
• Page Start: 47
• Page End: 62
• Publication Date: 2015-02
• Subjects: AAV adeno-associated virus -- CNS central nervous system -- DLB dementia with Lewy bodies -- ERAD endoplasmic reticulum associated-degradation -- ERT enzyme replacement therapy -- FDA Food and Drug Administration -- GBA1 lysosomal glucocerebrosidase gene -- GBA2 cytosolic glucocerebrosidase gene -- HDAC histone deacetylase -- iPSC induced pluripotent stem cells -- Lamp-2a lysosomal-associated membrane protein 2a -- LRRK2 leucine-rich repeat kinase 2 -- PCT pharmacological chaperone therapy -- PD Parkinson's disease -- RIPK3 receptor-interacting serine–threonine kinase 3 -- SNCA α-synuclein gene -- SRT substrate reduction therapy -- TFEB transcription factor EB -- VPS35 vacuolar protein sorting 35; GBA1 -- Glucocerebrosidase -- Gaucher disease -- Alpha-synuclein -- Parkinson's disease -- Dementia with Lewy bodies; Isofagomine (PubChem CID: 447607) -- NCGC00188758 (PubChem CID: 46907762) -- Miglustat (PubChem CID: 51634) -- Eliglustat (PubChem CID: 52918379); Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2014.12.001
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Gaucher disease is linked to the development of Parkinson's disease. GBA1 mutations are the most common risk factor for α-synuclein aggregation disorders. Glucocerebrosidase can affect α-synuclein proteostasis through various mechanisms. α-Synuclein accumulation decreases glucocerebrosidase, leading to a vicious cycle. Increasing glucocerebrosidase activity is a therapeutic approach for synucleinopathies. Abstract: Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene ( GBA1 ) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1 -related synucleinopathies, and potentially, for non- GBA1 -associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.