Defining the mechanisms of ataxin 2 polyglutamine expansions in Amyotrophic Lateral Sclerosis.

摘要

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, causes loss of voluntary movement and progressive paralysis that ultimately leads to death within 2 to 5 years of symptom onset. Riluzole, the only currently available treatment, extends life by only 3 months, emphasizing the need for better treatments and a cure for this devastating disease. ALS results from the degeneration of brain and spinal cord motor neurons, which are pathologically characterized by inclusions containing misfolded and aggregated TDP-43 protein. However, the pathogenic mechanisms underlying motor neuron death and TDP-43 pathology in ALS are not well understood. In this dissertation we report the discovery of an interaction between TDP-43 and the yeast gene PBP1 (human homolog: ataxin 2). Utilizing multiple genetic and human cellular model systems we characterized the interaction between TDP-43 and ataxin 2, and report that intermediate-length polyglutamine (polyQ) expansions in ataxin 2 are a genetic risk factor for ALS. The investigation of potential pathogenic mechanisms using cellular models and human post-mortem tissue led to the discovery that intermediate-length polyQ expansions in ataxin 2 result in an abnormal cellular stress response, including enhanced activation of caspase 3 and accumulation of a phosphorylated C-terminal fragment of TDP-43. Analysis of post-mortem tissue from ALS patients with and without ataxin 2 intermediate-length polyQ expansions found distinct TDP-43 pathology in cases with ataxin 2 involvement. Together, these results reveal a novel role for ataxin 2 in ALS and motor neuron degeneration and provide the first functional studies describing pathogenic mechanisms of ataxin 2 intermediate-length polyQ expansions and how they might impact TDP-43 pathology in ALS. Importantly, the data presented here advances our understanding of ALS etiology and expands our knowledge of genetic factors and protein misfolding in ALS, providing mechanistic information and cellular targets that will aid in development of therapeutics for ALS patients. Finally, the results in this dissertation define ataxin 2 as a complex genetic locus that will have novel implications for neurodegenerative disease classification, diagnosis, and treatment.