title: α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2.
abstract: Accumulating evidence from genetic and biochemical studies implicates dysfunction of the autophagic-lysosomal pathway as a key feature in the pathogenesis of Parkinson's disease (PD). Most studies have focused on accumulation of neurotoxic α-synuclein secondary to defects in autophagy as the cause of neurodegeneration, but abnormalities of the autophagic-lysosomal system likely mediate toxicity through multiple mechanisms. To further explore how endolysosomal dysfunction causes PD-related neurodegeneration, we generated a murine model of Kufor-Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with additional neurological features. KRS is caused by recessive loss-of-function mutations in the ATP13A2 gene encoding the endolysosomal ATPase ATP13A2. We show that loss of ATP13A2 causes a specific protein trafficking defect, and that Atp13a2 null mice develop age-related motor dysfunction that is preceded by neuropathological changes, including gliosis, accumulation of ubiquitinated protein aggregates, lipofuscinosis, and endolysosomal abnormalities. Contrary to predictions from in vitro data, in vivo mouse genetic studies demonstrate that these phenotypes are α-synuclein independent. Our findings indicate that endolysosomal dysfunction and abnormalities of α-synuclein homeostasis are not synonymous, even in the context of an endolysosomal genetic defect linked to Parkinsonism, and highlight the presence of α-synuclein-independent neurotoxicity consequent to endolysosomal dysfunction.
authors: Neuroscience Graduate Program, Medical Scientist Training Program, and Departments of Neurology and.
authors: Lauren R
authors: LR
authors: Kett
authors: Department of Development and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors: Barbara
authors: http://orcid.org/0000-0001-7003-5733
authors: B
authors: Stiller
authors: Departments of Neurology and.
authors: Megan M
authors: MM
authors: Bernath
authors: Department of Development and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors: Inmaculada
authors: I
authors: Tasset
authors: Departments of Neurology and Center for Motor Neuron Biology and Disease, and.
authors: Javier
authors: http://orcid.org/0000-0002-4257-1325
authors: J
authors: Blesa
authors: Departments of Neurology and Center for Motor Neuron Biology and Disease, and.
authors: Vernice
authors: V
authors: Jackson-Lewis
authors: Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032.
authors: Robin B
authors: RB
authors: Chan
authors: Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032.
authors: Bowen
authors: http://orcid.org/0000-0003-4421-9787
authors: B
authors: Zhou
authors: Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032.
authors: Gilbert
authors: G
authors: Di Paolo
authors: Departments of Neurology and Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, and.
authors: Serge
authors: S
authors: Przedborski
authors: Department of Development and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors: Ana Maria
authors: AM
authors: Cuervo
authors: Neuroscience Graduate Program, Departments of Neurology and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, dauer@med.umich.edu.
authors: William T
authors: WT
authors: Dauer
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics / Q000648:ultrastructure; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005106:Exploratory Behavior / Q000502:physiology; D019417:Hindlimb Suspension / Q000523:psychology; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000032:analysis; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D004856:Postural Balance / Q000235:genetics; D006180:Proton-Translocating ATPases; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D008055:Lipids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; C572751:ATP13A2 protein, mouse; D000251:Adenosine Triphosphatases; D006180:Proton-Translocating ATPases
keywords: ATP13A2; Parkinson's disease; autophagy; endolysosomal system; genetics