A G4C2?C4G2 repeat expansion in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases with no effective treatment. We have shown that sense and antisense RNA transcripts of the C9ORF72 expanded repeat undergo an unconventional mode of translation (RAN translation), resulting in the abnormal production of 5 """"""""c9RAN proteins"""""""" of repeating dipeptides. Using novel antibodies to each of the c9RAN proteins, our group and others have demonstrated that their expression is unique to patients with the C9ORF72 expansion (""""""""c9FTD/ALS"""""""" patients), and that c9RAN proteins form neuronal inclusions throughout the central nervous system. The identification of this neuropathological hallmark of c9FTD/ALS sheds new light on potential disease mechanisms and much needed biomarkers for c9FTD/ALS. Although c9RAN proteins associate with disease-specific inclusions in c9FTD/ALS, confirmatory data demonstrating toxicity are lacking. For instance, inclusions composed of certain c9RAN proteins are abundant in some vulnerable areas but not others. Nonetheless, no study has yet investigated the expression and solubility profile of all c9RAN proteins, nor evaluated whether expression of any c9RAN protein, either in soluble or insoluble form, correlates with neurodegeneration in various neuroanatomical regions of the central nervous system. Such a study, proposed herein, will provide much needed insight into the pathomechanisms of c9FTD/ALS and could influence the development of therapeutic strategies. Even as their contribution to neurodegeneration is being investigated, c9RAN proteins could prove useful as biomarkers for c9FTD/ALS. Immunoassays for the detection of c9RAN proteins in cerebrospinal fluid (CSF), and potentially in peripheral blood, would be the first disease-specific test available for any form of ALS and FTD other than DNA testing for known inherited forms of the disease. DNA testing, however, offers no clinical or prognostic information other than confirmation of the presence of a mutation. Through the development of sensitive immunoassays for each c9RAN protein, and the longitudinal collection of CSF, plasma and serum from c9ALS and c9ALS-FTD patients, along with longitudinal evaluations of neuromuscular, cognitive and behavioral status, we aim to assess whether any of the 5 c9RAN proteins can be used to diagnose and monitor disease activity. Of importance, our preliminary data indicate that poly(GP) c9RAN proteins are indeed detectable in c9ALS cerebrospinal fluid (CSF), which is a promising first step toward validating c9RAN proteins as disease biomarkers. Overall, the goals of the proposed project are to gain a better understanding of the potential role of c9RAN proteins in c9FTD/ALS pathogenesis, and to evaluate whether specific c9RAN proteins can serve as urgently needed biomarkers to aid in the diagnosis and estimation of prognosis of c9FTD/ALS patients.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative diseases with a common genetic cause: an expanded repeat in the C9ORF72 gene, which leads neurons to produce abnormal proteins referred to as c9RAN proteins. This project has two important goals;the first is to determine whether the presence of c9RAN proteins accounts for the loss of healthy neurons in the brain and spinal cord of affected patients. The second goal is to determine whether measuring c9RAN protein levels in patient spinal fluid or blood can be used as a test for diagnosing and monitoring disease progression, which is important for the correct clinical management of patients, and may provide a more efficient and objective way to evaluate experimental therapies in clinical trials.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Sutherland, Margaret L
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Mayo Clinic Jacksonville
United States
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Gendron, Tania F; Petrucelli, Leonard (2018) Disease Mechanisms of C9ORF72 Repeat Expansions. Cold Spring Harb Perspect Med 8:
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