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Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1931-6. doi: 10.1073/pnas.1520335113. Epub 2016 Feb 2.

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

Author information

1
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129; The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
2
The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
3
Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478;
4
Center for Stem Cell Biology and Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, NY 10065; Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, NY 10065.
5
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129; The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; krainc@northwestern.edu.

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.

KEYWORDS:

Parkinson's disease; induced pluripotent stem cells; long-term midbrain culture; protein trafficking; synucleinopathies

PMID:
26839413
PMCID:
PMC4763774
DOI:
10.1073/pnas.1520335113
[Indexed for MEDLINE]
Free PMC Article

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