Molecular Signatures of Amyotrophic Lateral Sclerosis in Skeletal Muscle

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that inexorably leads to progressive weakness and death. There is no specific biomarker for this disease, and the diagnosis is often delayed as clinical and electrophysiological examinations are often inconclusive in the early stages. Furthermore, once a diagnosis is established, the current tools to track patients are insensitive for the timely detection of disease improvement or worsening. A biomarker that can facilitate diagnosis, track disease progression, or both, would fill a large clinical gap in ALS management, and expedite clinical trials of novel therapies. The long term goal of this application is to identify molecular signatures in muscle of ALS patients that can serve as disease biomarkers. In ALS, changes occur in skeletal muscle prior to motor neuron death and clinical onset, such as structural changes in the neuromuscular junction, muscle restricted mitochondrial dysfunction, and fiber atrophy. Muscle is the "end organ" affected by the degenerative process of ALS and is the most accessible for molecular study. Here we hypothesize that gene expression patterns in muscle from patients with ALS contain molecular signatures that can serve as biomarkers of the disease. This hypothesis is based on preliminary data we obtained using next generation deep sequencing on muscle samples of clinically well characterized ALS patients. Using non-ALS disease- and normal control samples, we identified over 300 unique targets in ALS samples, including isoform variances, that will serve as the basis of study for this application. We are wel positioned to carry out this study because of the large neuromuscular patient population, including ALS and ALS mimics, and our oversight of the electrodiagnostic and muscle histology laboratories. Here, we will further investigate our molecular targets with the following two specific aims: Specific Aims: 1. To validate ALS-specific targets and isoform variances identified by deep sequencing by performing PCR analysis of a large cohort of ALS and non-ALS muscle samples. 2: To assess protein expression of validated targets in muscle tissues from ALS patients and correlate targets with muscle samples from the G93A SOD1 ALS mouse.