Concomitant Gain and Loss of Function Pathomechanisms in C9ORF72 Amyotrophic Lateral Sclerosis

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2021 Feb 23

PMID 33619157

Citations 10

Authors

Arun Pal

Benedikt Kretner

Masin Abo-Rady

Hannes GlaB

Banaja P Dash

Marcel Naumann

Julia Japtok

Nicole Kreiter

Ashutosh Dhingra

Peter Heutink

Tobias M Bockers

Rene GuNTHER

Jared Sterneckert

Andreas Hermann

Affiliations

Soon will be listed here.

Abstract

Intronic hexanucleotide repeat expansions (HREs) in are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient-albeit to a smaller extent-to induce premature distal axonal trafficking deficits and increased DSBs.

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