Abstract
Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.
Keywords:
D409V; GBA1; GCase; Lewy body; Parkinson’s disease; glucosylceramide; glucosylsphingosine; network model; neurodegenerative disease; transmission.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Astrocytes / cytology
-
Astrocytes / metabolism*
-
Astrocytes / pathology
-
Cerebral Cortex / cytology
-
Cerebral Cortex / metabolism
-
Cerebral Cortex / pathology
-
Disease Susceptibility
-
Genetic Predisposition to Disease
-
Glucosylceramidase / genetics*
-
Glucosylceramidase / metabolism
-
HEK293 Cells
-
Hippocampus / cytology
-
Hippocampus / metabolism
-
Hippocampus / pathology
-
Humans
-
Lewy Body Disease / genetics
-
Lewy Body Disease / metabolism
-
Lewy Body Disease / pathology
-
Mesencephalon / cytology
-
Mesencephalon / metabolism
-
Mesencephalon / pathology
-
Mice
-
Mice, Transgenic
-
Neurons / cytology
-
Neurons / metabolism*
-
Neurons / pathology
-
Parkinson Disease / genetics
-
Parkinson Disease / metabolism
-
Parkinson Disease / pathology
-
Parkinsonian Disorders / genetics*
-
Parkinsonian Disorders / metabolism
-
Parkinsonian Disorders / pathology
-
Primary Cell Culture
-
Protein Aggregation, Pathological / genetics*
-
Protein Aggregation, Pathological / metabolism
-
Protein Aggregation, Pathological / pathology
-
Synucleinopathies / genetics
-
Synucleinopathies / metabolism
-
Synucleinopathies / pathology
-
alpha-Synuclein / metabolism*
Substances
-
alpha-Synuclein
-
GBA protein, human
-
Glucosylceramidase