Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis
Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.
Authors
- Jessica Rosati (ORCID: https://orcid.org/0000-0002-4483-386X)
- Antonella Falconieri (ORCID: https://orcid.org/0000-0002-2377-1399)
- Manuela Basso (ORCID: https://orcid.org/0000-0002-9278-8960)
- Samuele Metti (ORCID: https://orcid.org/0000-0003-1215-0551)
- Agostino Marasco (ORCID: https://orcid.org/0009-0008-6875-653X)
- Emanuela Zuccaro (ORCID: https://orcid.org/0000-0001-8978-7206)
- Marika Tonellato (ORCID: https://orcid.org/0000-0001-8402-7136)
- Carlo Biz (ORCID: https://orcid.org/0000-0001-8517-0057)
- Charles H. Large (ORCID: https://orcid.org/0000-0001-9814-7737)
- Martin J. Gunthorpe (ORCID: https://orcid.org/0000-0002-0216-1735)
- Valentina Adami (ORCID: https://orcid.org/0000-0002-0617-9393)
- Maria Pennuto (ORCID: https://orcid.org/0000-0001-8634-0767)
- Lisa Gambarotto
- Nadia Pilati (ORCID: https://orcid.org/0000-0002-1525-333X)
- Assunta Pozzuoli (ORCID: https://orcid.org/0000-0001-9905-0363)
- Angelo Poletti (ORCID: https://orcid.org/0000-0002-8883-0468)
- Roberta Andreotti (ORCID: https://orcid.org/0000-0002-2814-2743)
- Aishwarya Aravamudhan (ORCID: https://orcid.org/0009-0002-4584-8147)
- Elisa Belluzzi (ORCID: https://orcid.org/0000-0003-1129-2574)
- Ornella Rossetto (ORCID: https://orcid.org/0000-0002-6113-3857)
- Caterina Marchioretti (ORCID: https://orcid.org/0000-0002-2290-6845)
- Manuela Marabita
- Pietro Ruggieri (ORCID: https://orcid.org/0000-0001-9617-9882)
- Paolo Bonaldo (ORCID: https://orcid.org/0000-0002-9571-8140)
- Kyung Ho Park
- Giuseppe Alvaro
- Gianni Sorarú (ORCID: https://orcid.org/0000-0001-9691-6328)
- Sara Vianello
- S. William Zito
Institutions
- University of Padua (IT)
- Chungbuk National University (KR)
- University of Trento (IT)
- Casa Sollievo della Sofferenza (IT)
- Autifony Therapeutics (United Kingdom) (GB)
- Veneto Institute of Molecular Medicine (IT)
- Stevenage Bioscience Catalyst (GB)
- Ospedale San Paolo (IT)
- Città della Speranza Foundation (IT)
Publication Details
- Journal
- Acta Neuropathologica Communications
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1186/s40478-025-02067-z
- Citations
- 1
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- Muscular Dystrophy Association
- Università degli Studi di Padova