A diagnostic biomarker for amyotrophic lateral sclerosis

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Amyotrophic Lateral Sclerosis (ALS), a fatal adult onset motor neuron disease characterized by selective loss of upper and lower motor neurons, and Fronto-Temporal Dementia (FTD), a common form of dementia characterized by a progressive deterioration in behaviour, personality and/or language, share a common disease spectrum. The neuropathology involving Transactivation response element DNA-binding protein 43 (TDP-43) occurs in nearly all cases of ALS and large proportion of FTD, neurodegenerative diseases currently without effective therapy. The overarching goals of this proposal are to develop a diagnostic test for ALS. By developing monoclonal antibodies designed to recognize cryptic exon encode peptides, we show that loss of TDP-43 splicing repression occurs in pre-symptomatic C9ORF72 patients. This novel finding would support the idea that loss of TDP-43 function occurs during early stage of disease. In this application, we will establish this important mechanistic insight and develop a diagnostic test for prodromal phase of ALS, a critical unmet need in the field relevant for recruitment of patients at their earliest stage of disease and for monitoring target engagement in clinical trials. Proposed studies in this application will have important implications for developing a diagnostic test for the prodromal phase of ALS.