Seminars

Dr. Maya Maor-Nof, Department of Genetics, Stanford University School of Medicine
03/01/2022 13:00

Title: The diverse cellular and molecular mechanisms driving neuronal and axonal degeneration
Zoom: https://technion.zoom.us/j/98391777547


Abstract: Aberrations in protein folding, processing and degradation are common features of neurodegenerative diseases, resulting in their accumulation. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia(FTD) are two neurodegenerative diseases that share genetic and neuropathological features. The most common genetic cause of both ALS and FTD is a hexanucleotide repeat expansion in the C9orf72 gene. In both diseases aggregation of the protein TDP-43 is the major pathological hallmark. How theC9orf72 hexanucleotide repeat expansion and the TDP-43 protein accumulations contribute to neurodegeneration is largely unknown. To study the cellular mechanisms driving neurodegeneration, I developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons in response to pathogenic protein accumulation. I provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 nucleotide repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor p53. Ablating p53 in mice completely rescued neurons from cell death and axonal degeneration and markedly increased survival in a C9orf72 mouse model. Furthermore, p53 reduction was sufficient to rescueC9orf72 ALS patient iPSC-derived motor neurons from degeneration. Mechanistically, p53 is stabilized, binds to DNA and activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate neurodegenerative mechanisms are dynamically regulated through transcription factor binding events controlling gene expression programs and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

Host: Prof. Benjamin Podbilewicz

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