Abstract

Motor Neurone Disease (MND) is a fatal, incurable progressive neuromuscular paralysis. While many cases of MND are sporadic, several genes are implicated in familial forms of the disease. One of the major genetic causes of MND is mutation in the superoxide dismutase 1 (SOD1) gene. There are over 150 mutations spanning the entire protein sequence suggesting dysfunction arises from improper folding of the protein, which is evidenced by the appearance of intracellular aggregates in motor neurons and other cell types at later stages of disease. The disease is not caused by loss of normal protein function and instead is a gain of a new inherent toxic attribute, further indicative of SOD1 misfolding conferring new stresses to cell functions. We propose that the proteostasis imbalance created by expression of mutant SOD1 leads to a reduced operation of an extensive network of housekeeping functions that are dependent on proteostasis machinery such as ubiquitin proteasome system, which we predict to cause a decline in cell health and heighten sensitivity to further stresses that triggers neurodegeneration.