Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia
Abstract
Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1 , encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BK G354S ) in KCNMA1 , in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BK G354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BK G354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BK G354S channel, but not the BK WT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 04, 2020
- Source ID
- 10.1073/pnas.1920008117
Entities
People
- Cenfu Wei
- Christopher M Gomez
- Francisco Bezanilla
- Joao L. Carvalho-de-souza
- Julia Staisch
- Michael Xu
- Naileth Gonzalez
- Natalie Petrossian
- Ramon Latorre
- Timothy Hain
- Tomoya Kubota
- Willy Carrasquel-ursulaez
- Xiaofei Du
- Yenisleidy Lorenzo
Organizations
- Air Force Office of Scientific Research
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- Northwestern University
- University of Chicago
- University of Valparaíso