Research article summary (published 14 Sep 2009):

Striatal expression of a calmodulin fragment improved motor function, weight loss, and neuropathology in the R6/2 mouse model of Huntington's disease.

Full Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (htt). Increasing evidence suggests that transglutaminase (TGase) plays a critical role in the pathophysiology of HD possibly by stabilizing monomeric, polymeric and aggregated htt. We previously reported that in HEK293 and SH-SY5Y cells expression of a calmodulin (CaM)-fragment, consisting of amino acids 76-121 of CaM, decreased binding of CaM to mutant htt, TGase-modified htt and cytotoxicity associated with mutant htt and normalized intracellular calcium release. In this study, an adeno-associated virus (AAV) that expresses the CaM-fragment was injected into the striatum of HD transgenic R6/2 mice. The CaM-fragment significantly reduced body weight loss and improved motor function as indicated by improved rotarod performance, longer stride length, lower stride frequency, fewer low mobility bouts and longer travel distance than HD controls. A small but insignificant increase in survival was observed in R6/2 mice with CaM-fragment expression. Immunoprecipitation studies show that expression of the CaM-fragment reduced TGase-modified htt in the striatum of R6/2 mice. The percentage of htt-positive nuclei and the size of intranuclear htt aggregates were reduced by the CaM-fragment without striatal volume changes. The effects of CaM-fragment appear to be selective, as activity of another CaM-dependent enzyme, CaM-dependent kinase II, was not altered. Moreover, inhibition of TGase-modified htt was substrate-specific since overall TGase activity in the striatum was not altered by treatment with the CaM-fragment. Together, these results suggest that disrupting CaM-htt interaction may provide a new therapeutic strategy for HD.

Author information

Author/s: Dai, Ying (Y); Dudek, Nichole L (NL); Li, Qian (Q); Fowler, Stephen C (SC); Muma, Nancy A (NA);

Affiliation: Neuroscience Graduate Program, Loyola University Medical Center, Maywood, Illinois 60153, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Sep; vol 29 (issue 37) : pp 11550-9

Dates: Created 2009/09/17; Completed 2009/10/02;

PMID: 19759302, status: MEDLINE (last retrieval date: 10/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Analysis of Variance Animals Behavior, Animal - physiology Body Weight - genetics; physiology Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism Calmodulin - genetics; metabolism Corpus Striatum - metabolism Dependovirus - genetics Disease Models, Animal GTP-Binding Proteins - metabolism Gait - genetics Gene Expression Regulation, Enzymologic - genetics Green Fluorescent Proteins - genetics

Green Fluorescent Proteins - genetics Huntington Disease - genetics; metabolism; pathology; physiopathology Immunoprecipitation - methods Locomotion - genetics; physiology Male Mice Mice, Transgenic Motor Activity Peptide Fragments - genetics; metabolism Rotarod Performance Test Serotonin Plasma Membrane Transport Proteins - genetics; metabolism Transglutaminases - metabolism Trinucleotide Repeat Expansion - genetics

Associated Chemicals: Calmodulin (0) ; Peptide Fragments (0) ; Serotonin Plasma Membrane Transport Proteins (0) ; Slc6a4 protein, mouse (0) ; Green Fluorescent Proteins (147336-22-9) ; transglutaminase 2 (EC 2.3.2.-) ; Transglutaminases (EC 2.3.2.13) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; GTP-Binding Proteins (EC 3.6.1.-)

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