Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis.

Autor:	Pal A; Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany., Kretner B; Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.; Center for Regenerative Therapies TU Dresden (CRTD), Technische Universität Dresden, Dresden, Germany., Abo-Rady M; Center for Regenerative Therapies TU Dresden (CRTD), Technische Universität Dresden, Dresden, Germany., Glaβ H; Translational Neurodegeneration Section 'Albrecht-Kossel,' Department of Neurology, and Center for Transdisciplinary Neuroscience (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany., Dash BP; Translational Neurodegeneration Section 'Albrecht-Kossel,' Department of Neurology, and Center for Transdisciplinary Neuroscience (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany., Naumann M; Translational Neurodegeneration Section 'Albrecht-Kossel,' Department of Neurology, and Center for Transdisciplinary Neuroscience (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany., Japtok J; Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany., Kreiter N; Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany., Dhingra A; German Center for Neurodegenerative Diseases (DZNE), Genome Biology of Neurodegenerative Diseases, Tübingen, Germany., Heutink P; German Center for Neurodegenerative Diseases (DZNE), Genome Biology of Neurodegenerative Diseases, Tübingen, Germany.; Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Böckers TM; Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany., Günther R; Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.; German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany., Sterneckert J; Center for Regenerative Therapies TU Dresden (CRTD), Technische Universität Dresden, Dresden, Germany., Hermann A; Translational Neurodegeneration Section 'Albrecht-Kossel,' Department of Neurology, and Center for Transdisciplinary Neuroscience (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany Andreas.Hermann@med.uni-rostock.de.; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2021 Feb 22; Vol. 4 (4). Date of Electronic Publication: 2021 Feb 22 (Print Publication: 2021).
DOI:	10.26508/lsa.202000764
Abstrakt:	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. (© 2021 Pal et al.)
Databáze:	MEDLINE
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