IS THERE A ROLE FOR ENDOPLASMIC RETICULUM STRESS IN THE PATHOGENESIS OF ALS?

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Motor neuron disease (MND) is a devastating and rapidly progressing adult onset disease; most patients die 2-5 years after diagnosis. MND is characterized by the death of specific cells, called 'motor neurons' within the nervous system. Unfortunatley, MND currently has an unknown cause and no effective treatment. This proposal aims to study the mechanisms that trigger degeneration of motor neurons in MND. Some forms of MND are inherited and linked to mutations in a protein called SOD1, but how the mutations lead to cell death is unclear. However, SOD1 mutants are known to clump together in large aggregates and this is linked to toxicity. In a previous study, we found that normally SOD1 is secreted from the cell where it can protect the motor neuron from oxidative damage. However SOD1 mutants are not secreted as well as the normal protein, leaving the cell vulnerable to damage. In addition, the compartment of the cell responsible for secretion,the 'endoplasmic reticulum' (ER), is under stress due to secretory dysfunction of mutant SOD1. Our data suggest that this ER stress leads to the activation of 'cell suicide' pathways, leading to death of the motor neuron. However, very little is known about how molecular events in the ER lead to cell death in MND. This proposal will examine these processes in detail. In other studies, we found that a molecule called 'PDI' inhibits mutant SOD1 from aggregation and is made in large quantities in our laboratory models of MND. This proposal will determine if PDI is potentially a new therapeutic target for MND due its ability to protect the cell from the toxic effects of SOD1 aggregation. Our findings are both novel and exciting and propose previously unexplored mechanisms of disease and new theraputic targets. Once we understand the basic mechanisms occuring in the motor neuron, which we can design specific therapies to halt the progression of the disease and prolong the life of human MND patients.