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

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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.

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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

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Acknowledgments

We are grateful to the Harvard Brain Tissue Resource Center (NIH) for providing the human brain tissue samples for these investigations. We thank dbGaP for granting ZL access to GWAS datasets (Project# 1542). This work was supported by NIH Morris K. Udall Parkinson’s Disease Research Centers of Excellence P50NS39793 (OI) and 2P50NS071674 (JMV, ERM), by the Consolidated Anti-Aging Foundation, the Orchard Foundation, the Cooper Family and the Hansen Family (OI), National Natural Science Foundation 81400940 (XW) and by the Michael J. Fox Foundation and American Parkinson Disease Association (ZL), and by the Shervert Frazier Research Institute (EAB, BMC). We thank Dr. Randy Blakely (Vanderbilt) for the BY200 strain, Dr. Gian Garriga (UC Berkeley) for the GR1333 strain, and Theresa Stiernagle at the C. elegans Genetics Center for worm strains used in this work. This work is dedicated to the memory of Dr. Edgar (Ned) A. Buttner, who passed away on October 15, 2015, for his inspiring enthusiasm, warm collegiality, and excellence in science.

Authors’ Contributions

XW: Performed the experiments, analyzed the data, performed statistical analysis, and drafted the manuscript.

NL: Performed the experiments.

NX: Performed the experiments.

QY: Performed the experiments.

JL: Performed the experiments.

JY: Performed the experiments.

HQ: Contribution of vital reagents/tools.

TW: Contribution of vital reagents/tools.

HJC: Performed statistical analysis.

OI: Obtained funding.

JMV: Performed statistical analysis and obtaining funding.

ERM: Analyzed the data; performed statistical analysis and obtained funding.

YZ: Performed the experiments.

BMC: Drafted the manuscript and obtained funding.

EAB: Conceived and designed the experiments, analyzed the data, drafted the manuscript and obtained funding.

ZL: Conceived and designed the experiments, performed statistical analysis, analyzed the data, drafted the manuscript and obtained funding.

All the authors contributed to revision and have approved the final manuscript.

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    Authors and Affiliations

    1. School of Public Health, Xinxiang Medical University, 453003, Xinxiang, China

      Xin Wang

    2. Department of Psychiatry, Harvard Medical School, Boston, MA, 02114, USA

      Xin Wang, Nuomin Li, Nian Xiong, Qi You, Jie Li, Jinlong Yu, Ying Zhao, Bruce M. Cohen, Edgar A. Buttner & Zhicheng Lin

    3. Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA

      Xin Wang, Nian Xiong, Ole Isacson, Bruce M. Cohen, Edgar A. Buttner & Zhicheng Lin

    4. Laboratory of Psychiatric Neurogenomics, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA

      Nuomin Li, Nian Xiong, Qi You, Ying Zhao & Zhicheng Lin

    5. School of Life Science, Beijing Institute of Technology, 100081, Beijing, China

      Nuomin Li & Hong Qing

    6. Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02114, USA

      Nian Xiong, Ole Isacson & Zhicheng Lin

    7. Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China

      Nian Xiong & Tao Wang

    8. Department of Neurology, Hubei Zhongshan Hospital, Wuhan, 430074, Hubei, China

      Qi You

    9. Tianjin Mental Health Center, Tianjin, 300222, China

      Jie Li

    10. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

      Heather J. Cordell

    11. Neuroregeneration Laboratories, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA

      Ole Isacson

    12. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

      Jeffery M. Vance & Eden R. Martin

    13. School of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, China

      Ying Zhao

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    Xin Wang, Nuomin Li and Nian Xiong contributed equally to this work.

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    Wang, X., Li, N., Xiong, N. et al. Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson’s Disease. Mol Neurobiol 54, 2878–2888 (2017). https://doi.org/10.1007/s12035-016-9861-y

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