Miro1 deficiency in amyotrophic lateral sclerosis

Fan Zhang,Jun Liu,Wenzhang Wang,Sandra L Siedlak,Xinglong Wang,Xiongwei Zhu,George Perry,Yingchao Liu,Keji Jiang

doi:10.3389/fnagi.2015.00100

Abstract

Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

Highlights

Amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases characterized by progressive neurodegeneration of motor neurons in the brainstem and spinal cord (Rowland and Shneider, 2001)
Reduced Expression of Miro1 in Spinal Cords but not Brains of SOD1G93A Transgenic Mice Since the widely used transgenic mice expressing ALSassociated SOD1 G93A mutant (SOD1G93A mice) develop phenotypes closely mimicking fALS and sporadic ALS (sALS), we studied the expression of Miro1 in the spinal cord and brain tissues from these mice
We show that the expression of Miro1 is significantly reduced in the spinal cords of sALS patients, SOD1G93A mice, TDP-43M337V mice and mice infused with glutamate

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases characterized by progressive neurodegeneration of motor neurons in the brainstem and spinal cord (Rowland and Shneider, 2001). 5–10% of ALS cases are familial (fALS), of which most are associated with repeat expansions of the C9ORF72 gene or mutations in genes encoding copper–zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-43) or fused in sarcoma (FUS; Al-Chalabi et al, 2012). Accumulation of mitochondria was reported in the proximal axons of motor neurons of ALS patients, indicating the possible impairment of mitochondrial transport (Sasaki and Iwata, 1996). Impaired mitochondrial movement and altered mitochondrial distribution were noted in motor neurons expressing ALS-associated mutant SOD1 G93A or TDP-43 M337V in vitro and in mice (De Vos et al, 2007; Bilsland et al, 2010; Wang et al, 2013; Magrané et al, 2014). Despite expanding evidence for the important role of mitochondrial trafficking deficits in the pathogenesis of ALS (Shi et al, 2010), the underlying mechanism is still not clear

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