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      Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration

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          Significance

          The neuropathological spectrum of Parkinson’s disease (PD) brains harboring VPS35 mutations is not yet clear since only a single mutation carrier has been evaluated at autopsy. D620N VPS35 knockin mice developed here represent one of the first models of inherited PD that develop the robust and progressive degeneration of nigral dopaminergic neurons. Furthermore, these mice develop robust and widespread tau-positive pathology and axonal damage but lack signs of Lewy pathology positive for α-synuclein. VPS35 knockin mice indicate that the D620N mutation is sufficient for the development of tau abnormalities but not α-synuclein. The D620N VPS35 knockin mice provide an important new tool for distinguishing the neuropathological consequences and mechanisms of familial VPS35 mutations, including the intersection with other PD genetic risk factors.

          Abstract

          Mutations in the vacuolar protein sorting 35 ortholog ( VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein–positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.

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          Most cited references 63

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          Alpha-synuclein in Lewy bodies.

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            alpha-Synuclein locus triplication causes Parkinson's disease.

             A Singleton (2003)
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              Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

              We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                19 March 2019
                6 March 2019
                6 March 2019
                : 116
                : 12
                : 5765-5774
                Affiliations
                aCenter for Neurodegenerative Science, Van Andel Research Institute , Grand Rapids, MI 49503;
                bDepartment of Translational Science and Molecular Medicine, Michigan State University , Grand Rapids, MI 49503;
                cDivision of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University , Grand Rapids, MI 49503
                Author notes
                1To whom correspondence should be addressed. Email: Darren.Moore@ 123456vai.org .

                Edited by Anders Björklund, Lund University, Lund, Sweden, and approved February 13, 2019 (received for review August 30, 2018)

                Author contributions: X.C., J.K.K., J.M., J.W.L., and D.J.M. designed research; X.C., J.K.K., E.T.W., N.L., A.C.-S., and J.W.L. performed research; L.M., V.L., and J.M. contributed new reagents/analytic tools; X.C., A.C.-S., L.M., V.L., J.W.L., and D.J.M. analyzed data; and X.C., J.M., and D.J.M. wrote the paper.

                Article
                201814909
                10.1073/pnas.1814909116
                6431187
                30842285
                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                Page count
                Pages: 10
                Product
                Funding
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: NS105432
                Award Recipient : Darren J Moore
                Funded by: Parkinson's Disease Foundation (PDF) 100001288
                Award ID: PF-FBS-1768
                Award Recipient : Xi Chen
                Funded by: Michael J. Fox Foundation for Parkinson's Research (MJFF) 100000864
                Award ID: N/A
                Award Recipient : Darren J Moore
                Funded by: Van Andel Research Institute (VARI) 100006019
                Award ID: N/A
                Award Recipient : Darren J Moore
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

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