Neurodegenerative diseases are characterized by adult-onset progressive degeneration of specific neuronal populations. The molecular mechanisms underlying neurodegenerative diseases are poorly understood, and as a consequence, there are currently no or only minimally effective (disease-modifying) treatments available. Thus, there is a high unmet medical need, and neurodegenerative diseases are a high burden to patients and their families and result in high costs for society.
This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy, which is caused by selective degeneration of peripheral motor and sensory neurons, leading to progressive muscle weakness and wasting, steppage gait, often foot deformities, and sensory dysfunction. Currently, there is not a single FDA- or EMA-approved drug available for CMT.
The overall goal of this project was to unravel the molecular mechanisms underlying specific genetic forms of CMT, caused by mutations in cytoplasmic tRNA synthetases (CMT-aaRS). tRNA synthetases constitute the largest protein family implicated in CMT, because dominantly inherited (heterozygous) mutations in 8 distinct tRNA synthetase genes all cause CMT. tRNA synthetases are enzymes which link amino acids to their cognate tRNA, thus catalyzing the first step of protein biosynthesis. We had previously shown that expression of CMT-mutant versions tRNA synthetases in Drosophila motor or sensory neurons resulted in a significant reduction of global protein synthesis.
The specific aims of the project were to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, the major goal was to unravel the molecular mechanism underlying CMT-aaRS.
