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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS089979-01
Application #
8805433
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sutherland, Margaret L
Project Start
2014-09-15
Project End
2016-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Gendron, Tania F; Chew, Jeannie; Stankowski, Jeannette N et al. (2017) Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med 9:
Gendron, Tania F; C9ORF72 Neurofilament Study Group; Daughrity, Lillian M et al. (2017) Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis. Ann Neurol 82:139-146
Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F et al. (2016) Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons. Neuron 92:383-391
Zhang, Yong-Jie; Gendron, Tania F; Grima, Jonathan C et al. (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci 19:668-677
Jiang, Jie; Zhu, Qiang; Gendron, Tania F et al. (2016) Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron 90:535-50
Chew, Jeannie; Gendron, Tania F; Prudencio, Mercedes et al. (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348:1151-4
Gendron, Tania F; van Blitterswijk, Marka; Bieniek, Kevin F et al. (2015) Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol 130:559-73
O'Rourke, Jacqueline G; Bogdanik, Laurent; Muhammad, A K M G et al. (2015) C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. Neuron 88:892-901
Peters, Owen M; Cabrera, Gabriela Toro; Tran, Helene et al. (2015) Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron 88:902-909
Tran, Helene; Almeida, Sandra; Moore, Jill et al. (2015) Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron 87:1207-1214

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