Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson’s Disease

Xin Wang, Nuomin Li, Nian Xiong, Qi You, Jie Li, Jinlong Yu, Hong Qing, Tao Wang, Heather J. Cordell, Ole Isacson, Jeffery M Vance, Eden R Martin, Ying Zhao, Bruce M. Cohen, Edgar A. Buttner, Zhicheng Lin

Research output: Contribution to journalArticle

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalMolecular Neurobiology
DOIs
StateAccepted/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

Wang, X., Li, N., Xiong, N., You, Q., Li, J., Yu, J., Qing, H., Wang, T., Cordell, H. J., Isacson, O., Vance, J. M., Martin, E. R., Zhao, Y., Cohen, B. M., Buttner, E. A., & Lin, Z. (Accepted/In press). Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson’s Disease. Molecular Neurobiology, 1-11. https://doi.org/10.1007/s12035-016-9861-y