FAIM Proteostasis in ALS - Summary The broad, long term objectives of this project are to elucidate the mechanisms by which abnormal protein aggregation is handled at the cellular level, and to determine the relationship between abnormal protein aggregation/disaggregation and neurodegenerative disease. The specific focus of the present proposal is to study the inter-relationships among a unique proteostatic agent (FAIM), abnormal protein aggregation, and ALS disease. The clinical picture of ALS is grim, with motor neuron loss, progressive paralysis, and death, all occurring during a brief course of 2-5 years duration. The etiology of ALS remains unknown, and no inciting insult or preceding illness has been identified. Elucidation of ALS pathogenesis is hampered by the sporadic nature of most cases, although a minority (familial ALS or FALS) is attributable to mutation in one of several genes such as the gene encoding SOD1. Importantly, regardless of sporadic or familial origin, all cases of ALS are characterized by the presence of abnormal protein aggregates. Because such aggregates are known to be toxic, this dysfunctional protein behavior is thought to be a key pathogenic element in ALS. It has been suggested that discovery of an agent that prevents or reverses protein aggregation could constitute a means to ameliorate disease in ALS. FAIM may be such an agent. Although originally cloned as Fas Apoptosis Inhibitory Molecule, we recently reported that FAIM manifests important proteostatic activity. In the face of various forms of stress, FAIM inhibits endogenous protein aggregation and, in keeping with this, FAIM counteracts loss of viability in stressed cells and animals. Moreover, FAIM specifically inhibits aggregation of mutant SOD1 and disas- sembles established mutant SOD1 aggregates in cell-free systems. We now propose further study of FAIM in relation to ALS. 1) We will examine the capacity of FAIM to influence aggregation of ALS-associated mutant SOD1 protein in human motor neuron cells differentiated from healthy control iPSC in which FAIM has been deleted or overexpressed. 2) We will examine the capacity of FAIM to improve ALS, by studying disease onset, severity and outcome, plus tissue histologic examination, in mutant SOD1 ALS disease model mice in which FAIM has been deleted or overexpressed, both generally and in neurons. These studies will likely show that FAIM can oppose mutant protein aggregation in human neurons and can improve ALS disease in mice. Such results would provide proof-of- principle and support for the hypothesis that FAIM can benefit other familial, and non-familial, forms of ALS through its proteostatic activity. Further, such results would fuel important continued study of FAIM in cellular stress conditions and in other neurodegenerative diseases. This work could suggest a potential therapeutic role for FAIM in ameliorating ALS and possibly other neurodegenerative diseases.
