Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia.

Autor: Du X; Department of Neurology, The University of Chicago, Chicago, IL 60637., Carvalho-de-Souza JL; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.; Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637., Wei C; Department of Neurology, The University of Chicago, Chicago, IL 60637., Carrasquel-Ursulaez W; Centro Interdisciplinario de Neurociencia de Valparaìso, Facultad de Ciencias, Universidad de Valparaiso, Valparaíso 2340000, Chile., Lorenzo Y; Centro Interdisciplinario de Neurociencia de Valparaìso, Facultad de Ciencias, Universidad de Valparaiso, Valparaíso 2340000, Chile., Gonzalez N; Centro Interdisciplinario de Neurociencia de Valparaìso, Facultad de Ciencias, Universidad de Valparaiso, Valparaíso 2340000, Chile., Kubota T; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.; Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637., Staisch J; Department of Neurology, The University of Chicago, Chicago, IL 60637., Hain T; Department of Neurology, Northwestern University, Chicago, IL 60611., Petrossian N; Department of Neurology, The University of Chicago, Chicago, IL 60637., Xu M; Department of Neurology, The University of Chicago, Chicago, IL 60637., Latorre R; Centro Interdisciplinario de Neurociencia de Valparaìso, Facultad de Ciencias, Universidad de Valparaiso, Valparaíso 2340000, Chile., Bezanilla F; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.; Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637.; Centro Interdisciplinario de Neurociencia de Valparaìso, Facultad de Ciencias, Universidad de Valparaiso, Valparaíso 2340000, Chile., Gomez CM; Department of Neurology, The University of Chicago, Chicago, IL 60637; cgomez@neurology.bsd.uchicago.edu.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 17; Vol. 117 (11), pp. 6023-6034. Date of Electronic Publication: 2020 Mar 04.
DOI: 10.1073/pnas.1920008117
Abstrakt: 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.
Competing Interests: The authors declare no competing interest.
Databáze: MEDLINE
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