Verapamil Ameliorates Motor Neuron Degeneration and Improves Lifespan in the SOD1 Mouse Model of ALS by Enhancing Autophagic Flux

Overview

Journal Aging Dis

Specialty Geriatrics

Date 2019 Dec 3

PMID 31788329

Citations 25

Authors

Xiaojie Zhang

Sheng Chen

Kaili Lu

Feng Wang

Jiangshan Deng

Zhouwei Xu

Xiuzhe Wang

Qinming Zhou

Weidong Le

Yuwu Zhao

Affiliations

Soon will be listed here.

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 Ca dependent autophagic pathway in ALS by using the L-type channel Ca blocker, verapamil. We have found that verapamil significantly delayed disease onset, prolonged the lifespan and extended disease duration in SOD1 mice. Furthermore, verapamil administration rescued motor neuron survival and ameliorated skeletal muscle denervation in SOD1 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 SOD1 mice. Furthermore, we have demonstrated that verapamil reduced endoplasmic reticulum stress and suppressed glia activation in SOD1 mice. Collectively, our study indicated that verapamil is neuroprotective in the ALS mouse model and the Ca-dependent autophagic pathway is a possible therapeutic target for the treatment of ALS.

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