Use of induced pluripotent stem cells to study mechanims of familial and sporadic

Harvard University, Cambridge MA

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Abstract

Abstract[unreadable] ALS is a progressive neurodegenerative disease characterized by the loss of upper and[unreadable] lower motor neurons, culminating in muscle wasting and death from respiratory failure[unreadable] [1-3]. The majority of ALS cases are sporadic, with 90% of patients presenting disease[unreadable] symptoms with no family history of ALS. The remaining 10% of ALS patients are[unreadable] diagnosed with familial ALS [1-3]. Approximately 25% of the familial cases of ALS are[unreadable] caused by mutations in the dominantly inherited gene encoding super oxide dismutase[unreadable] (SOD) [4]. Identification of pathogenic alleles of SOD1 has led to the production of[unreadable] transgenic mouse and rat models for the study of ALS [5-8]. Overproduction of[unreadable] pathogenic human SOD1 protein in mice and rats leads to late onset, progressive[unreadable] neurodegenerative disease [5, 6, 8]. Studies of the SOD1 animal models have led to the[unreadable] identification and study of intrinsic pathogenic characteristics of ALS motor neurons[unreadable] including the formation of protein aggregates, cytoskeletal abnormalities, proteasome[unreadable] dysfunction and increased sensitivity to cell death signals [1, 5]. Although much has[unreadable] been learned in these animal models of the familial disease, very little is known about[unreadable] the sporadic disease because of the lack of a suitable in vivo system. We propose to[unreadable] make use of recent advances in stem cell research [9-13] to generate and study human[unreadable] motor neurons in culture derived from fibroblasts donated by sporadic ALS patients.[unreadable] These motor neurons will be used in long term cell cultures to examine[unreadable] pathophysiological hallmarks of the sporadic disease, including analysis of protein[unreadable] aggregates, morphologically altered mitochondria, electrophysiological properties, gene[unreadable] expression analyses, and examination of patterns of alternative pre-mRNA splicing. If[unreadable] successful, these studies may provide important new mechanistic insights into sporadic[unreadable] ALS, and provide cell-based assays for drug screening.