CORE C G4C2 repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating diseases with no effective treatment. Success in developing a treatment for ?c9ALS/FTD? will require a better understanding of disease pathomechanisms, the identification of molecular pathways amenable to therapeutic targeting, and the development of biomarkers to track disease progression and to confirm target engagement of potential therapies. The studies outlined in Projects 1, 2 and 3 aim to fill these needs, and the Human Validation Core (Core C) will work closely with Project investigators to facilitate these important studies. In addition to providing post-mortem tissues to Projects 1, 2 and 3, Core C will conduct a thorough neuropathological and biochemical analysis of these patient samples, including the quantification of TDP-43, P62 and dipeptide repeat (DPR) protein pathology, microgliosis and astrogliosis, and repeat length. Core C will similarly characterize brain tissues from (G4C2)149 mice used in Projects 1 and 3, and measure DPR protein levels in neurons differentiated from patient-derived induced pluripotent stem cells used in Project 2. These data will serve as valuable traits for the proteomic and transcriptomic studies conducted in all three projects to discover pathological mechanisms relevant to disease, and biomarkers for use in clinical trials. Furthermore, Core C will play a significant role in validating, at the protein level, expression changes of genes or proteins that associate with ALS genotypes or phenotypes, and that may define pathophysiological pathways linked to c9ALS. This will be done with independent methods of protein detection and using tissues from discovery series and validation series. Indeed, to ensure that the collection of post-mortem tissues from C9orf72 repeat expansion carriers continues to grow, Core C will work closely with Core B to obtain rapid autopsies of patients enrolled in clinical studies and provide diagnostic evaluations. In this fashion, we will further increase the number of patients from whom both antemortem cerebrospinal fluid (CSF) and postmortem brain tissue are available ? important resources for comparing brain and CSF proteomes. With regards to the latter, Core C will help Project 3 home in on promising candidate biomarkers that warrant investigation in CSF, and assist in determining whether their top candidates could serve as CSF biomarkers for c9ALS/FTD.
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