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Glucocerebrosidase is shaking up the synucleinopathies.

ABSTRACT: The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronopathic forms. Like many monogenic diseases, the correlation between clinical manifestations and molecular genotype is not straightforward. There is now a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more prevalent multifactorial disorders including Parkinson's disease and other synucleinopathies. In this review we discuss recent studies advancing our understanding of the cellular relationship between glucocerebrosidase and ?-synuclein, the potential impact of established and emerging therapeutics for Gaucher disease for the treatment of the synucleinopathies, and the role of lysosomal pathways in the pathogenesis of these neurodegenerative disorders.

SUBMITTER: Siebert M

PROVIDER: S-EPMC3999712 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Glucocerebrosidase is shaking up the synucleinopathies.

Siebert Marina M Sidransky Ellen E Westbroek Wendy W

Brain : a journal of neurology 20140214 Pt 5

The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronop ...[more]

PMID: 24531622

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Project description:Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.

Project description:Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA) constitute the three major neurodegenerative disorders referred to as synucleinopathies because both genetic and pathological results implicate the ?-synuclein protein in their pathogenesis. PD and DLBD are recognized as closely related diseases with substantial clinical and pathological overlap. MSA, on the other hand, has a distinctive clinical presentation and neuropathological profile. In this review, we will summarize the evidence linking ?-synuclein to these three disorders. Hundreds of patients with point or copy number mutations in the gene encoding ?-synuclein, SNCA, have been reported in the literature in association with hereditary, autosomal dominant forms of PD, DLBD, or neurodegenerative disease with parkinsonism. The copy number mutations show a dosage effect with age at onset and severity correlating with the number of extra copies of SNCA a patient carries. Common variation in and around the SNCA gene has also been found by genome-wide association studies to be associated with increased risk for apparently sporadic PD, with some evidence that these variants exert their effect through modest increases in ?-synuclein expression. Complementing the genetic evidence linking ?-synuclein to PD and DLBD is the pathological finding that ?-synuclein is a major constituent of Lewy bodies and Lewy neurites in the brains of patients with the common sporadic form of PD. On the other hand, there is little genetic evidence linking SNCA to MSA despite strong neuropathological evidence of ?-synuclein aggregation in oligodendroglial cells in MSA patients. Evidence is now emerging that ?-synuclein aggregates can have different protein conformations, referred to as strains, similar to what has been shown in prion disease. The different phenotypes in hereditary PD/DLBD versus MSA are likely, therefore, to be the result not only of how specific mutations affect protein expression and turnover, but also a more complex interaction between intrinsic and extrinsic factors governing aggregation and strain formation.

Dataset Information

Glucocerebrosidase is shaking up the synucleinopathies.

Publications

Glucocerebrosidase is shaking up the synucleinopathies.

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