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

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Abstract

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.

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Acknowledgements

This work was supported by the National Institute of Neurological Disorders and Stroke grant R01NS092823 (JRM) and R01NS076054 (DK).

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  1. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 12-369, Chicago, IL, 60611, USA

    Iva Stojkovska, Dimitri Krainc & Joseph R. Mazzulli

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  1. Iva Stojkovska
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  2. Dimitri Krainc
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Correspondence to Joseph R. Mazzulli.

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JRM and DK are co-founders of Lysosomal Therapeutics, Inc., a company that uses lysosomal biology to develop treatments for neurodegenerative disease.

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Stojkovska, I., Krainc, D. & Mazzulli, J.R. Molecular mechanisms of α-synuclein and GBA1 in Parkinson’s disease. Cell Tissue Res 373, 51–60 (2018). https://doi.org/10.1007/s00441-017-2704-y

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