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Related Experiment Video

Updated: Nov 18, 2025

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Open Access: A Role for p53 in c9ALS/FTD?

Charlotte M Fare¹, James Shorter¹

¹Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Trends in Genetics : TIG

|February 8, 2021

Summary

This summary is machine-generated.

Toxic protein poly(PR) from C9orf72 repeat expansions drives neurodegeneration in ALS/FTD by altering neuronal epigenetics and promoting cell death pathways.

Keywords:

PUMA TDP-43 c9ALS/FTD dipeptide-repeat protein p53 poly(PR)

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Area of Science:

Neuroscience
Molecular Biology
Genetics

Background:

Poly(PR), a toxic dipeptide-repeat protein, is translated from the G4C2 repeat expansion in C9orf72.
This expansion is a key genetic cause of C9orf72-associated amyotrophic lateral sclerosis/frontotemporal dementia (c9ALS/FTD).
The precise mechanisms by which poly(PR) causes neurodegeneration are not fully understood.

Purpose of the Study:

To elucidate the molecular mechanisms underlying poly(PR)-induced neurodegeneration.
To investigate the role of poly(PR) in altering neuronal epigenetics.
To identify downstream pathways activated by poly(PR) that lead to neuronal cell death.

Main Methods:

Utilized cellular and animal models relevant to c9ALS/FTD.
Employed techniques to assess epigenetic modifications in neurons exposed to poly(PR).
Investigated the activation of apoptotic pathways, including p53 and PUMA.

Main Results:

Poly(PR) was shown to remodel the neuronal epigenome.
This epigenetic remodeling promotes proapoptotic p53 activity.
The PUMA protein, downstream of p53, was identified as a key mediator driving neurodegeneration.

Conclusions:

Poly(PR) exerts its neurotoxic effects by altering the neuronal epigenome.
The p53-PUMA apoptotic pathway is a critical mechanism through which poly(PR) causes neurodegeneration.
These findings provide new insights into the pathogenesis of c9ALS/FTD and potential therapeutic targets.