C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress

M E Cicardi; J H Hallgren; D Mawrie; K Krishnamurthy; S S Markandaiah; A T Nelson; V Kankate; E N Anderson; P Pasinelli; U B Pandey; C M Eischen; D Trotti

doi:10.1016/j.isci.2023.107505

C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress

iScience. 2023 Jul 28;26(9):107505. doi: 10.1016/j.isci.2023.107505. eCollection 2023 Sep 15.

Authors

Affiliations

¹ Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
² Center for Neuroscience, Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
³ Sidney Kimmel Cancer Center, Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is aberrantly translated in the sense and antisense directions into dipeptide repeat proteins, among which poly proline-arginine (PR) displays the most aggressive neurotoxicity in-vitro and in-vivo. PR partitions to the nucleus when heterologously expressed in neurons and other cell types. We show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR strongly accumulates in the nucleolus, a nuclear structure critical in regulating the cell stress response. We determined that, in neurons, PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels also prevented PR-mediated neurotoxicity both in in-vitro and in-vivo models. We investigated if PR could induce the senescence phenotype in neurons. However, we did not observe any indications of such an effect. Instead, we found evidence for the induction of programmed cell death via caspase-3 activation.

Keywords: Cellular neuroscience; Molecular neuroscience.

Abstract

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