Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.

Abstract

Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease.

• Authors: Ana T Simões, Nélio Gonçalves, Arnulf Koeppen, Nicole Déglon, Sebastian Kügler, Carlos Bandeira Duarte, Luís Pereira de Almeida
• Journal: Brain : a journal of neurology (Brain) Vol. 135 Issue Pt 8 Pg. 2428-39 (Aug 2012) ISSN: 1460-2156 [Electronic] England
• PMID: 22843411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Glycoproteins
• Neuroprotective Agents
• Nuclear Proteins
• Transcription Factors
• calpain inhibitors
• calpastatin
• Ataxin-3
• Atxn3 protein, mouse
• Calpain

Topics

• Active Transport, Cell Nucleus (genetics)
• Adult
• Animals
• Ataxin-3
• Brain Chemistry (genetics)
• Calcium-Binding Proteins (physiology)
• Calpain (antagonists & inhibitors, genetics, metabolism)
• Female
• Glycoproteins (antagonists & inhibitors, biosynthesis, physiology)
• Humans
• Machado-Joseph Disease (enzymology, metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Mutation (physiology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Nuclear Proteins (genetics, metabolism)
• Proteolysis
• Transcription Factors (genetics, metabolism)