α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 113

Pages Range: 1931-1936

Journal Issue: 7

DOI: 10.1073/pnas.1520335113

Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

Authors with CRIS profile

Friederike Zunke

Involved external institutions

Memorial Sloan Kettering Cancer Center US United States (USA) (US) Harvard University US United States (USA) (US) Northwestern University US United States (USA) (US)

How to cite

APA:

Mazzulli, J.R., Zunke, F., Isacson, O., Studer, L., & Krainc, D. (2016). α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proceedings of the National Academy of Sciences of the United States of America, 113(7), 1931-1936. https://dx.doi.org/10.1073/pnas.1520335113

MLA:

Mazzulli, Joseph R., et al. "α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models." Proceedings of the National Academy of Sciences of the United States of America 113.7 (2016): 1931-1936.

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