Differential regulation of kidins220 isoforms in Huntington’s disease.

Differential regulation of kidins220 isoforms in Huntington’s disease.

Publication date: Jul 02, 2019

Huntington’s disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific since Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD. This article is protected by copyright. All rights reserved.

Concepts Keywords
Atrophy C33
Brain Neuron
Calpain Calpain
Carboxy Terminal Peptidase
Cognitive
Downregulation
Exon
Huntington
Isoform
Isoforms
KDa
Membrane
Neurodegeneration
Neurodegenerative
Neurons
Neuroprotective
Neurotrophic
Neurotrophin
Pathogenic
Pathologies
Progressive
Protease
Protein
Proteolysis
Splicing
Striatum
Substrate
Vivo

Semantics

Type Source Name
drug DRUGBANK Ketamine
gene UNIPROT CKLF
gene UNIPROT CD82
disease MESH Multiple
gene UNIPROT KIDINS220

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