Genetics of Motor Neuron Diseases

Abstract

Motor neuron diseases, also known as MNDs, are a group of extremely severe neurological conditions that, in most cases, result in death. These diseases are primarily characterised by the gradual degeneration and/or loss of motor neurons in the brainstem and spinal cord regions. Genetic mutations are one of the main triggers of MND pathogenesis, and researchers have identified more than 100 different genes in humans that have been altered. Previous studies have shown that many of the enzymatic transcriptional products produced by the defective or mutated genes that cause MNDs are involved in the dysregulation of several key intracellular and molecular pathways that are essential for proper motor neuron functioning. These include RNA transport and splicing, protein homeostasis, microglial cell activation, mitochondrial functions, axonal protein transport, protein folding and many more. Key Concepts Motor neuron disease is a fatal neurodegenerative condition that affects motor neurons in the central nervous system. Genetic factors play a major role in the initiation and progression of motor neuron disease. Over the past few years, hundreds of genes that play causative roles in motor neuron disorders have been discovered. Identifying novel genes or rare genetic variants involved in motor neuron disease pathophysiology is extremely vital. The use of various high‐throughput gene sequencing techniques has been shown to be an effective tool for discovering genes related to motor neuron diseases. Alterations in the expression of genes in motor neuron disease cause dysregulation of several intracellular pathways that are essential for healthy motoneuron functioning. The mechanism underlying the death of motor neurons is influenced by a number of different cellular and molecular processes. Toxic gain‐of‐function or loss‐of‐function of a specific protein causes abnormalities in synapse mechanisms, which leads to the degeneration or death of motor neurons. Even though the first case of motor neuron disease was documented more than a century ago, there is still no effective treatment or a viable cure available for the disease. At present, managing disease symptoms and providing palliative care are still the main goals of motor neuron disease therapy.