Increased ROS-Dependent Fission of Mitochondria Causes Abnormal Morphology of the Cell Powerhouses in a Murine Model of Amyotrophic Lateral Sclerosis.

Jan Stein,Hilal Cihankaya,Bernd Walkenfort,Konstanze F Winklhofer,Pascal Röderer,Mike Hasenberg,Johann Matschke,Veronika Matschke,Verian Bader,Carsten Theiss,Claudio Cabello-Verrugio

doi:10.1155/2021/6924251

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in humans and remains to have a fatal prognosis. Recent studies in animal models and human ALS patients indicate that increased reactive oxygen species (ROS) play an important role in the pathogenesis. Considering previous studies revealing the influence of ROS on mitochondrial physiology, our attention was focused on mitochondria in the murine ALS model, wobbler mouse. The aim of this study was to investigate morphological differences between wild-type and wobbler mitochondria with aid of superresolution structured illumination fluorescence microscopy, TEM, and TEM tomography. To get an insight into mitochondrial dynamics, expression studies of corresponding proteins were performed. Here, we found significantly smaller and degenerated mitochondria in wobbler motor neurons at a stable stage of the disease. Our data suggest a ROS-regulated, Ox-CaMKII-dependent Drp1 activation leading to disrupted fission-fusion balance, resulting in fragmented mitochondria. These changes are associated with numerous impairments, resulting in an overall self-reinforcing decline of motor neurons. In summary, our study provides common pathomechanisms with other ALS models and human ALS cases confirming mitochondria and related dysfunctions as a therapeutic target for the treatment of ALS.

Highlights

Amyotrophic lateral sclerosis (ALS) is the most common systemic disease of the motor system
We compared the mitochondrial network of 50 motor neurons from WT and wobbler diseased (WR) of three independent preparations with aid of superresolution microscopy with structured illumination in combination with the analysis software Imaris 9.2.1
The present study focused on the morphological analysis of the mitochondrial network and individual mitochondria in motor neurons of wobbler mice, an ALS animal model, in context of previous studies discovering elevated reactive oxygen species (ROS) levels in wobbler spinal cords at the stable phase of the disease (p40)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common systemic disease of the motor system. The annual incidence rate in Europe is 2.2 per 100,000 inhabitants per year [1]. It is mainly classified in a familial and sporadic form. The disease is characterized by bilateral degeneration of cells from tractus corticospinalis, in the nuclei of cranial motoric nerves as well as motor neuronal cells in the anterior horn of the spinal cord [2]. The degeneration of the first motor neuron leads to progressive spastic paresis and painful muscle cramps combined with hyperreflexia, pseudobulbar paralysis, and pyramidal path signs [3]. In the course of time, these symptoms are masked by the degeneration of the second motor neuron.

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