Verapamil Ameliorates Motor Neuron Degeneration and Improves Lifespan in the SOD1G93A Mouse Model of ALS by Enhancing Autophagic Flux.

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

doi:10.14336/ad.2019.0228

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder caused by selective degeneration of motor neurons in the brain and spinal cord
Mounting evidence support the view that abnormal protein aggregation is involved in the pathogenesis of both familial and sporadic ALS [3, 4]
Abnormalities of Ca2+ homeostasis contributed to the SOD1 aggregation within specific motor neurons (MNs) [28] the effects of channel Ca2+ blockers (CCBs) in the pathology of ALS has not yet been elucidated

Summary

Introduction

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. We have detected the role of the Ca2+ dependent autophagic pathway in ALS by using the L-type channel Ca2+ blocker, verapamil. 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. Our findings and other previous studies have demonstrated the accumulation of AVs in MNs of SOD1G93A mice and ALS patients [8, 9]. It has been reported that verapamil causes an activation of autophagy and induction of an autophagic flux by reducing the level of intracellular Ca2+ [19]. Verapamil was found to show neuroprotective effects through novel anti-inflammatory mechanisms in an in vitro model of Parkinson's disease [23]

Methods

Results

Conclusion