Sema3A Facilitates a Retrograde Death Signal in ALS Diseased Motor Neurons Via CRMP4-Dynein Complex Formation

Roy Maimon¹, Lior Ankol¹, Elizabeth Tank³, Tal Gradus Pery¹, Yarden Opatosky², Sami Barmada³, Martin Balastik⁴, Eran Perlson¹

¹Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

²The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Israel

³Department of Neurology, University of Michigan, Ann Arbor, US

⁴Institue of Physiology CAS, Praha, Cheque republic

Abstract-
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with selective dysfunction; it causes the death of motor neurons (MNs). In spite of some progress, currently no effective treatment is available for ALS. Before such treatment can be developed, a more thorough understanding of ALS pathogenesis is required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS pathology via secretion of destabilizing factors such as Sema3A; these factors trigger axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on the molecular mechanism by which muscle contribute to MNs loss in ALS. We identified CRMP4 as part of a retrograde death signal generated in response to muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1^G93A) and human-derived (C9orf72) ALS models. Introducing peptides that interfere with CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN loss in ALS.