Verapamil ameliorates motor neuron degeneration and improves lifespan in the SOD1G93A mouse model of als by enhancing autophagic flux

Xiaojie Zhang, Sheng Chen, Kaili Lu, Feng Wang, Jiangshan Deng, Zhouwei Xu, Xiuzhe Wang, Qinming Zhou, Weidong Le, Yuwu Zhao

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder caused by selective degeneration of motor neurons in the brain and spinal cord. Our previous studies indicated that abnormal protein aggregation and dysfunctional autophagic flux might contribute to the disease pathogenesis. In this study, we have detected the role of the Ca2+ dependent autophagic pathway in ALS by using the L-type channel Ca2+ blocker, verapamil. We have found that verapamil significantly delayed disease onset, prolonged the lifespan and extended disease duration in SOD1G93A mice. Furthermore, verapamil administration rescued motor neuron survival and ameliorated skeletal muscle denervation in SOD1G93A mice. More interestingly, verapamil significantly reduced SOD1 aggregation and improved autophagic flux, which might be mediated the inhibition of calpain 1 activation in the spinal cord of SOD1G93A mice. Furthermore, we have demonstrated that verapamil reduced endoplasmic reticulum stress and suppressed glia activation in SOD1G93A mice. Collectively, our study indicated that verapamil is neuroprotective in the ALS mouse model and the Ca2+-dependent autophagic pathway is a possible therapeutic target for the treatment of ALS.

Original languageEnglish (US)
Pages (from-to)1159-1173
Number of pages15
JournalAging and Disease
Volume10
Issue number6
DOIs
StatePublished - 2019

Keywords

  • Amyotrophic lateral sclerosis
  • Autophagy
  • Calpain 1
  • Neurodegeneration
  • Verapamil

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cell Biology

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