Molecular mechanisms underlying neuromuscular dysfunction in ALS and CMT

Abstract

Neurodegeneration is a common feature across a broad spectrum of chronic, currently incurable conditions. At present, interventions that modify or prevent the progression of neurodegenerative diseases are either non-existent or have very limited beneficial effects. One reason for why such interventions are yet to be discovered is the limited understanding of the molecular mechanisms underlying the pathophysiology of neurodegeneration. The goal of this thesis is to contribute to unravelling the molecular changes underlying two currently incurable neurodegenerative diseases with overlapping pathomechanisms: amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) peripheral neuropathy. ALS is the most common adult onset motor neuron disease, characterized by muscle weakness and paralysis, followed by death due to respiratory failure. CMT is the most frequent group of inherited peripheral neuropathy. While ALS is defined by selective upper and lower motor neurons loss, CMT affects both peripheral motor and sensory neurons. Consequently, CMT manifests clinically not only as distal muscle weakness, but also sensory loss among other symptoms. Despite selective motor neuron loss, microglia, astrocytes and oligodendrocytes have been implicated in ALS. However, it is controversial whether skeletal muscle contributes to ALS pathogenesis, as previous evidence is rather conflicting. Therefore, this thesis addresses a key question in the field: does skeletal muscle tissue contribute to FUS-associated ALS pathogenesis? To understand which molecular alterations mediate muscle-intrinsic/-derived toxicity and could be subject to future therapeutic target discovery, this thesis presents the optimization and development of innovative RNA sequencing techniques to explore the transcriptome at the synapse between motor neurons and skeletal muscle. In addition, this thesis proposes a new molecular mechanism underlying Gars-associated CMT and explores the therapeutic potential of elevating tRNA levels. The work described in this thesis illustrates the importance of understanding molecular derailments in ALS and CMT, both in motor neurons and adjacent cell types, for the development of therapeutic strategies.