» Articles » PMID: 37426070

Viewpoint: Spinocerebellar Ataxias As Diseases of Purkinje Cell Dysfunction Rather Than Purkinje Cell Loss

Overview
Specialty Molecular Biology
Date 2023 Jul 10
PMID 37426070
Authors
Affiliations
Soon will be listed here.
Abstract

Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases mostly affecting cerebellar Purkinje cells caused by a wide variety of different mutations. One subtype, SCA14, is caused by mutations of Protein Kinase C gamma (PKCγ), the dominant PKC isoform present in Purkinje cells. Mutations in the pathway in which PKCγ is active, i.e., in the regulation of calcium levels and calcium signaling in Purkinje cells, are the cause of several other variants of SCA. In SCA14, many of the observed mutations in the PKCγ gene were shown to increase the basal activity of PKCγ, raising the possibility that increased activity of PKCγ might be the cause of most forms of SCA14 and might also be involved in the pathogenesis of SCA in related subtypes. In this viewpoint and review article we will discuss the evidence for and against such a major role of PKCγ basal activity and will suggest a hypothesis of how PKCγ activity and the calcium signaling pathway may be involved in the pathogenesis of SCAs despite the different and sometimes opposing effects of mutations affecting these pathways. We will then widen the scope and propose a concept of SCA pathogenesis which is not primarily driven by cell death and loss of Purkinje cells but rather by dysfunction of Purkinje cells which are still present and alive in the cerebellum.

Citing Articles

Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.

Li Z, Du X, Yang Y, Zhang L, Chen P, Kan Y Brain. 2024; 148(3):817-832.

PMID: 39315766 PMC: 11884698. DOI: 10.1093/brain/awae304.


Toll-like receptor 4 deficiency in Purkinje neurons drives cerebellar ataxia by impairing the BK channel-mediated after-hyperpolarization and cytosolic calcium homeostasis.

Zhu J, Qiu W, Wei F, Zhang J, Yuan Y, Liu L Cell Death Dis. 2024; 15(8):594.

PMID: 39147737 PMC: 11327311. DOI: 10.1038/s41419-024-06988-w.


Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia.

Sekerkova G, Kilic S, Cheng Y, Fredrick N, Osmani A, Kim H Neurobiol Dis. 2024; 195:106492.

PMID: 38575093 PMC: 11089908. DOI: 10.1016/j.nbd.2024.106492.

References
1.
Yan H, L Pablo J, Pitt G . FGF14 regulates presynaptic Ca2+ channels and synaptic transmission. Cell Rep. 2013; 4(1):66-75. PMC: 3736584. DOI: 10.1016/j.celrep.2013.06.012. View

2.
Seki T, Matsubayashi H, Amano T, Shirai Y, Saito N, Sakai N . Phosphorylation of PKC activation loop plays an important role in receptor-mediated translocation of PKC. Genes Cells. 2005; 10(3):225-39. DOI: 10.1111/j.1365-2443.2005.00830.x. View

3.
Sullivan R, Yau W, OConnor E, Houlden H . Spinocerebellar ataxia: an update. J Neurol. 2018; 266(2):533-544. PMC: 6373366. DOI: 10.1007/s00415-018-9076-4. View

4.
Watson L, Bamber E, Parolin Schnekenberg R, Williams J, Bettencourt C, Lickiss J . Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44. Am J Hum Genet. 2017; 101(5):866. PMC: 5673670. DOI: 10.1016/j.ajhg.2017.10.008. View

5.
Nakazono A, Adachi N, Takahashi H, Seki T, Hamada D, Ueyama T . Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14. J Biol Chem. 2018; 293(38):14758-14774. PMC: 6153279. DOI: 10.1074/jbc.RA118.002913. View