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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 7; pp. 1931 - 1936
• Main Authors: Mazzulli, Joseph R., Zunke, Friederike, Isacson, Ole, Studer, Lorenz, Krainc, Dimitri
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16-02-2016; National Acad Sciences
• Subjects: alpha-Synuclein - physiology; Biological Sciences; Humans; Lysosomes - physiology; Mesencephalon - metabolism; Mesencephalon - pathology; Models, Biological; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Protein Transport; induced pluripotent stem cells; Parkinson's disease; protein trafficking; synucleinopathies; long-term midbrain culture
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1520335113

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.