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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-11 |
| Number of pages | 11 |
| Journal | Molecular Neurobiology |
| DOIs | |
| State | Accepted/In press - Mar 28 2016 |
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Keywords
- Association study
- Caenorhabditis elegans modeling
- Genetics
- Nuclear family study
- Parkinson’s disease
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
Cite this
Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson’s Disease. / Wang, Xin; Li, Nuomin; Xiong, Nian; You, Qi; Li, Jie; Yu, Jinlong; Qing, Hong; Wang, Tao; Cordell, Heather J.; Isacson, Ole; Vance, Jeffery M; Martin, Eden R; Zhao, Ying; Cohen, Bruce M.; Buttner, Edgar A.; Lin, Zhicheng.
In: Molecular Neurobiology, 28.03.2016, p. 1-11.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson’s Disease
AU - Wang, Xin
AU - Li, Nuomin
AU - Xiong, Nian
AU - You, Qi
AU - Li, Jie
AU - Yu, Jinlong
AU - Qing, Hong
AU - Wang, Tao
AU - Cordell, Heather J.
AU - Isacson, Ole
AU - Vance, Jeffery M
AU - Martin, Eden R
AU - Zhao, Ying
AU - Cohen, Bruce M.
AU - Buttner, Edgar A.
AU - Lin, Zhicheng
PY - 2016/3/28
Y1 - 2016/3/28
N2 - 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.
AB - 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.
KW - Association study
KW - Caenorhabditis elegans modeling
KW - Genetics
KW - Nuclear family study
KW - Parkinson’s disease
UR - http://www.scopus.com/inward/record.url?scp=84961653811&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961653811&partnerID=8YFLogxK
U2 - 10.1007/s12035-016-9861-y
DO - 10.1007/s12035-016-9861-y
M3 - Article
C2 - 27021023
AN - SCOPUS:84961653811
SP - 1
EP - 11
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
ER -