The Role of Lysosomal Glucocerebrosidase in Synucleinopathies

Project: Research project

Project Details


The synucleinopathies, including Dementia with Lewy bodies (DLB), Multiple system
atrophy (MSA), and Parkinson’s disease (PD), are a group of neurodegenerative
disorders characterized by the accumulation of alpa-synuclein (a-syn), a small neuralspecific
protein that aberrantly aggregates into amyloid fibrils that comprise Lewy
bodies, the characteristic pathological inclusions found in synucleinopathies. One of the
critical issues in PD research, as well as across several neurodegenerative disease
research areas, is how to target the specific toxic, pathogenic moiety for therapeutic
development. The in vivo processes and cellular factors that control the formation of asyn
toxic forms are largely unknown. The recent discovery of parkinsonism and Lewy
bodies in patients with Gaucher disease (GD), a rare lysosomal storage disorder
characterized by mutations in the gene (GBA1) encoding glucocerebrosidase (GC)ase,
suggests a link between lysosomal sphingolipid metabolism and a-syn aggregation. In
our preliminary data we show that depletion of GCase results in endogenous a-syn
accumulation and neurodegeneration in mouse and C. elegans models of GD.
Compromised GCase activity in neurons led to accumulation of the GCase substrate
glucosylceramide, diminished lysosomal function, and increased soluble a-syn oligomeric
intermediates that were neurotoxic. Importantly, we found that a-syn accumulation has
the ability to affect the lysosomal maturation and activity of normal GCase in neurons
and human brain, suggesting that GlcCer accumulation also plays a role in sporadic PD
and other synucleinopathies. The experiments proposed in this application will further
test the hypothesis that alterations in GlcCer metabolism contribute to the pathogenesis of
synucleinopathies. We will examine whether therapeutic targeting of mutated or normal
glucocerebrosidase to lysosomes prevents or diminishes formation of toxic alphasynuclein
oligomers and breaks the vicious cycle of alpha-synuclein aggregation and
toxicity. If successful, these studies will provide further validation for a role of
lysosomal GCase in synucleinopathies and identify a specific molecular pathway for the
development of new therapies for PD and related diseases characterized by accumulation
of a-syn.
Effective start/end date9/1/134/30/17


  • National Institute of Neurological Disorders and Stroke (5R01NS076054-06)


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