title: Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease.
abstract: The cytoskeleton not only provides structure, it is an active component of cell function, and in several neurodegenerative disorders, there is evidence of cytoskeletal collapse. Cytoskeletal proteins have been specifically implicated in the pathogenesis of Parkinson's disease (PD), where degeneration of dopaminergic (DA) neurons is the hallmark, but in which many factors may determine the resilience of DA neurons during aging and stress. Here we report that the human Microtubule Actin Cross-linking Factor 1 gene (MACF1), a downstream target of PD biochemical pathways, was significantly associated with PD in 713 nuclear families. A significant allelic association between PD and rs12118033, with P = 0.0098, was observed, and a P < 0.03 was observed in the association analysis by both a trend test and an allelic test. We further observed that it is the MACF1b isoform, not the MACF1a isoform, which is expressed in DA neurons from six human postmortem brains. In a Caenorhabditis elegans system, used to explore the effect of altered MACF1b on neurons, knockdown or knockout of the MACF1b orthologue vab-10 resulted in the selective loss of DA neurons, which validated MACF1's risk candidacy in PD. These findings strongly suggest that MACF1b may contribute to the genetic etiology and mechanistic causation of PD.
authors.affiliation: School of Public Health, Xinxiang Medical University, 453003, Xinxiang, China. xwang120@gmail.com.|Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA. xwang120@gmail.com.|Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA. xwang120@gmail.com.
authors.forename: Xin
authors.identifier: 0000-0003-4262-579X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|School of Life Science, Beijing Institute of Technology, 100081, Beijing, China.
authors.forename: Nuomin
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02114, USA.|Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Xiong
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|Department of Neurology, Hubei Zhongshan Hospital, Wuhan, 430074, Hubei, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: You
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Tianjin Mental Health Center, Tianjin, 300222, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.affiliation: School of Life Science, Beijing Institute of Technology, 100081, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.affiliation: Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02114, USA.|Neuroregeneration Laboratories, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
authors.affiliation: Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.affiliation: Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.|School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA.|Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Buttner
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA. zhicheng_lin@hms.harvard.edu.|Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA. zhicheng_lin@hms.harvard.edu.|Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA. zhicheng_lin@hms.harvard.edu.|Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02114, USA. zhicheng_lin@hms.harvard.edu.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D005190:Family; D005260:Female; D055785:Gene Knockdown Techniques; D055786:Gene Knockout Techniques; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; C095003:MACF1 protein, human; D008840:Microfilament Proteins; D020033:Protein Isoforms; C475260:VAB-10 protein, C elegans
keywords: Association study; Caenorhabditis elegans modeling; Genetics; Nuclear family study; Parkinson’s disease