Exploring neurofilament biology and autophagy in neuromuscular diseases:from Giant Axonal Neuropathy to Charcot-Marie-Tooth diseases

Description

Abstract Our group is interested in inherited neuromuscular diseases, and in particular in axonal forms of Charcot-Marie-Tooth diseases. Our focus is on a severe related form, called Giant Axonal Neuropathy (GAN), which causes rapid loss of sensori-motor capacities in the periphery and subsequently spreads widely to the central nervous system. Our group identified the GAN gene and its defective protein, the Gigaxonin-E3 ligase and developed diagnostic tools to discriminate GAN from related CMTs. Furthermore, we modelized GAN in patient’s cells, mouse and zebrafish to investigate the pathological dysfunctions and translate our research into therapeutic products. In particular, I will present our findings on the pivotal role of Gigaxonin-E3 ligase in controlling key biological processes: Neurofilament and more generally Intermediate Filament organization, autophagy induction, and Sonic Hedgehog mediated neuron specification. In addition, achievements in generating relevant therapeutic methodologies for GAN will be discussed. Considering the evolving landscape of CMTs, which now highlights central nervous system involvement and common functional modalities with GAN, we would like to propose GAN as a key CMT form to understand the complexity of CMT biology. Finally, I will present the new scientific directions we are undertaking, expanding from GAN to other CMT diseases, with neurofilaments at the center of our focus.

Mechanisms & functions 1. Sonic Hedgehog repression underlies gigaxonin mutation-induced motor deficits in giant axonal neuropathy. Arribat Y*, Mysiak KS*, Lescouzères L, Boizot A, Ruiz M, Rossel M, Bomont P. J Clin Invest. 2019 Dec 2;129(12):5312-5326 2. Gigaxonin E3 ligase governs ATG16L1 turnover to control autophagosome production. Scrivo A, Codogno P, Bomont P. Nat Commun. 2019 Feb 15;10(1):780. 3. Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. Mahammad S, et al. J Clin Invest. 2013 May;123(5):1964-75.

Diagnosis 4. The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test. Boizot A, Talmat-Amar Y, Morrogh D, Kuntz NL, Halbert C, Chabrol B, Houlden H, Stojkovic T, Schulman BA, Rautenstrauss B, Bomont P. Acta Neuropathol Commun. 2014 Apr 24;2:47.

Clinics & genetics 5. Giant Axonal Neuropathy. Kuhlenbäumer G, Timmerman V, Bomont P. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® . Seattle (WA): University of Washington, Seattle; 1993-2020. 6. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S, Tazir M, Demir E, Topaloglu H, Korinthenberg R, Tüysüz B, Landrieu P, Hentati F, Koenig M. Nat Genet. 2000 Nov;26(3):370-4.