Dramatic advances have been made in recent years in the identification of genes that cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two closely related neurodegenerative diseases. This includes at least three RNA binding proteins (TDP-43, FUS and MATR3) and a hexanucleotide expansion in RNA transcripts of the C9orf72 gene. These findings have focused much attention on understanding how changes in RNA metabolism might underlie these diseases. Although most cases of ALS are sporadic (no obvious familial inheritance), in almost all cases the TDP-43 protein is found in cytoplasmic inclusions in affected motor neurons, suggesting the functions of this protein are broadly relevant to ALS. We have characterized the functions of TDP-43 in a model system (C. elegans) and cell culture, and discovered that loss of this protein results in accumulation of double-stranded RNA (dsRNA) and abnormal processing of ribosomal RNA. The goal of this proposal is to determine if these changes in the metabolism of RNA play a role in ALS/FTD pathology. We will investigate the molecular mechanisms by which TDP-43 limits dsRNA, and seek to determine if loss of FUS and MATR3, or expression of the C9orf72 hexanucleotide expansion, have similar effects on RNA metabolism. The disease-associated cytoplasmic redistribution of TDP-43 will also be investigated, particularly in response to expression of the C9orf72 hexanucleotide expansion and the associated production of aggregation-prone poly-dipeptides. These studies will employ RNA interference, genetic mutations, immunocytochemistry, in situ hybridization, and deep sequencing to globally characterize RNAs (the transcriptome), using both human cell culture and C. elegans models. We will test the disease relevance of our findings by extending these studies to patient cells (fibroblasts and reprogrammed neurons) as well as pathological samples. In particular, we will test the hypothesis that the RNA changes we have identified may play a role in the neuroinflammation and astroglial dysfunction that has been implicated in ALS pathology.

Public Health Relevance

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia are fatal, currently untreatable neurodegenerative diseases. Although specific genes have been identified that can mutate to cause the familial versions of these diseases, the specific molecular and cellular defects that lead to pathology are unknown. The proposed studies will test a specific hypothesis about the cellular defects that underlie these conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063964-09
Application #
9514263
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sutherland, Margaret L
Project Start
2009-04-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Graduate Schools
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80303
Gendron, Tania F; Petrucelli, Leonard (2018) Disease Mechanisms of C9ORF72 Repeat Expansions. Cold Spring Harb Perspect Med 8:
Mordes, Daniel A; Prudencio, Mercedes; Goodman, Lindsey D et al. (2018) Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients. Acta Neuropathol Commun 6:55
Prudencio, Mercedes; Gonzales, Patrick K; Cook, Casey N et al. (2017) Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum Mol Genet 26:3421-3431
LaRocca, Thomas J; Martens, Christopher R; Seals, Douglas R (2017) Nutrition and other lifestyle influences on arterial aging. Ageing Res Rev 39:106-119
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
Kramer, Nicholas J; Carlomagno, Yari; Zhang, Yong-Jie et al. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353:708-12
Vatsavayai, Sarat C; Yoon, Soo Jin; Gardner, Raquel C et al. (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139:3202-3216
Todd, Tiffany W; Petrucelli, Leonard (2016) Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions. J Neurochem 138 Suppl 1:145-62
Tian, Feng; Yang, Wenlong; Mordes, Daniel A et al. (2016) Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat Commun 7:13283
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

Showing the most recent 10 out of 52 publications