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

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-B (P2))
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Wehrle, Janna P
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Amoroso, Mackenzie W; Croft, Gist F; Williams, Damian J et al. (2013) Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J Neurosci 33:574-86
Yamazaki, Tomohiro; Chen, Shi; Yu, Yong et al. (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2:799-806