Molecular mechanisms of α-synuclein and GBA1 in Parkinson’s disease

• Published in: Cell and tissue research Vol. 373; no. 1; pp. 51 - 60
• Main Authors: Stojkovska, Iva, Krainc, Dimitri, Mazzulli, Joseph R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-07-2018; Springer Nature B.V
• Subjects: alpha-Synuclein - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Disease; Glucosylceramidase; Glucosylceramidase - metabolism; Human Genetics; Humans; Lewy bodies; Lipid metabolism; Lysosomes - metabolism; Models, Biological; Molecular Medicine; Molecular modelling; Movement disorders; Mutation - genetics; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson Disease - therapy; Parkinson's disease; Protein transport; Protein turnover; Proteomics; Quality control; Review; Risk factors; Synuclein; Protein aggregation; Glucosylceramide; Lysosomal dysfunction; Neurodegeneration; Alpha (α)-synuclein
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-017-2704-y

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized pathologically by the presence of Lewy bodies comprised of insoluble alpha (α)-synuclein. Pathological, clinical and genetic studies demonstrate that mutations in the
GBA1
gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase) that is deficient in Gaucher’s disease, are important risk factors for the development of PD. The molecular mechanism for the association between these two diseases is not completely understood. We discuss several possible mechanisms that may lead to
GBA1
-related neuronal death and α-synuclein accumulation including disruptions in lipid metabolism, protein trafficking and impaired protein quality control mechanisms. Elucidating the mechanism between GCase and α-synuclein may provide insight into potential therapeutic pathways for PD and related synucleinopathies.