Molecular Neurobiology

, Volume 54, Issue 4, pp 2878–2888 | Cite as

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
Article

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.

Keywords

Association study Nuclear family study Genetics Parkinson’s disease Caenorhabditis elegans modeling 

Abbreviations

PD

Parkinson’s disease

MACF1

Microtubule actin cross-linking factor 1

SNP

Single nucleotide polymorphism

GAS2

Growth-Arrest-Specific Protein 2

LCM

Laser capture microdissection

APL

Association in the Presence of Linkage

geno-PDT

Genotype-pedigree disequilibrium test

QTDT

Quantitative transmission disequilibrium test

AAO

Age-at-onset

PCR

Polymerase chain reaction

NGM

Nematode growth medium

Supplementary material

12035_2016_9861_MOESM1_ESM.pdf (730 kb)
ESM 1(PDF 729 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Xin Wang
    • 1
    • 2
    • 3
  • Nuomin Li
    • 2
    • 4
    • 5
  • Nian Xiong
    • 2
    • 3
    • 4
    • 6
    • 7
  • Qi You
    • 2
    • 4
    • 8
  • Jie Li
    • 2
    • 9
  • Jinlong Yu
    • 2
  • Hong Qing
    • 5
  • Tao Wang
    • 7
  • Heather J. Cordell
    • 10
  • Ole Isacson
    • 3
    • 6
    • 11
  • Jeffery M. Vance
    • 12
  • Eden R. Martin
    • 12
  • Ying Zhao
    • 2
    • 4
    • 13
  • Bruce M. Cohen
    • 2
    • 3
  • Edgar A. Buttner
    • 2
    • 3
  • Zhicheng Lin
    • 2
    • 3
    • 4
    • 6
  1. 1.School of Public HealthXinxiang Medical UniversityXinxiangChina
  2. 2.Department of PsychiatryHarvard Medical SchoolBostonUSA
  3. 3.Mailman Research CenterMcLean HospitalBelmontUSA
  4. 4.Laboratory of Psychiatric NeurogenomicsMcLean HospitalBelmontUSA
  5. 5.School of Life ScienceBeijing Institute of TechnologyBeijingChina
  6. 6.Harvard NeuroDiscovery CenterHarvard Medical SchoolBostonUSA
  7. 7.Department of Neurology, Union HospitalHuazhong University of Science and TechnologyWuhanChina
  8. 8.Department of NeurologyHubei Zhongshan HospitalWuhanChina
  9. 9.Tianjin Mental Health CenterTianjinChina
  10. 10.Institute of Genetic MedicineNewcastle UniversityNewcastle upon TyneUK
  11. 11.Neuroregeneration LaboratoriesMcLean HospitalBelmontUSA
  12. 12.Hussman Institute for Human Genomics, Miller School of MedicineUniversity of MiamiMiamiUSA
  13. 13.School of PharmacyXinxiang Medical UniversityXinxiangChina

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