title: α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.
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.affiliation: 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;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.affiliation: The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors.forename: Friederike
authors.initials: F
authors.lastname: Zunke
authors.affiliation: Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478;
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
authors.affiliation: 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.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
authors.affiliation: 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.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology*; D008954:Models, Biological; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*; D021381:Protein Transport; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D051844:alpha-Synuclein
keywords: Parkinson's disease; induced pluripotent stem cells; long-term midbrain culture; protein trafficking; synucleinopathies
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