RT Journal Article
SR Electronic
T1 Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000764
DO 10.26508/lsa.202000764
VO 4
IS 4
A1 Arun Pal
A1 Benedikt Kretner
A1 Masin Abo-Rady
A1 Hannes Glaβ
A1 Banaja P Dash
A1 Marcel Naumann
A1 Julia Japtok
A1 Nicole Kreiter
A1 Ashutosh Dhingra
A1 Peter Heutink
A1 Tobias M Böckers
A1 René Günther
A1 Jared Sterneckert
A1 Andreas Hermann
YR 2021
UL https://www.life-science-alliance.org/content/4/4/e202000764.abstract
AB Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 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 C9ORF72 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 C9ORF72 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.