Delayed Disease Onset and Extended Survival in the SOD1^G93ARat Model of Amyotrophic Lateral Sclerosis after Suppression of Mutant SOD1 in the Motor Cortex

Abstract

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1 G93A rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1 G93A rats through targeted delivery of AAV9 -SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.

Introductory Chapter: Introduction to Update in Amyotrophic Lateral Sclerosis and Review of this Condition in Sportsmen

“…In our series of patients, we found that professional boxing and rugby players are the most common to be associated with ALS, but we have to mention that our job is done in a semi-rural setting where other sport modalities are not practiced. We support the hypotheses that cortical dysfunction caused by any kind of injury should be taken into consideration as part of the pathophysiology of ALS [50][51][52], until proven otherwise.…”

Does dysfunction of the mirror neuron system contribute to symptoms in amyotrophic lateral sclerosis?

“…A significant difficulty in identifying impairment of the MNS in ALS, and other neurodegenerative diseases, is the slowly progressive nature of these disorders, and their prolonged preclinical period (Eisen et al , 2014a, Thomsen et al , 2014. This presumably enables a degree of adaption, masking subtle abnormalities in the MNS, which might otherwise induce clinical deficits.…”

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

“…This is the case for MBLN1 overexpression in a DM1 disease in vivo model [73] and for Purα in C9ORF72 [78].…”

“…A recent in vivo study is of particular interest because it provides evidence for a significant delay in disease onset and increased survival in a SOD1-G93A rat model by targeting mutant SOD1 in upper motor neurons by means of an AAV9-shRNA [73]. In general, the use of viral vectors has made the development of gene therapy against mutant SOD1-linked ALS possible, providing encouraging results in several studies in which good tolerability profiles were also reported [70,73,74].…”

“…In general, the use of viral vectors has made the development of gene therapy against mutant SOD1-linked ALS possible, providing encouraging results in several studies in which good tolerability profiles were also reported [70,73,74].…”