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.
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.
|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