Thiol-disulfide Oxidoreductases TRX1 and TMX3 Decrease Neuronal Atrophy in a Lentiviral Mouse Model of Huntington’s Disease

Abstract

Huntington's disease (HD) is caused by a trinucleotide CAG repeat in the huntingtin gene (HTT) that results in expression of a polyglutamine-expanded mutant huntingtin protein (mHTT). N-terminal fragments of mHTT accumulate in brain neurons and glia as soluble monomeric and oligomeric species as well as insoluble protein aggregates and drive the disease process. Decreasing mHTT levels in brain provides protection and reversal of disease signs in HD mice making mHTT a prime target for disease modification. There is evidence for aberrant thiol oxidation within mHTT and other proteins in HD models. Based on this, we hypothesized that a specific thiol-disulfide oxidoreductase exists that decreases mHTT levels in cells and provides protection in HD mice. We undertook an in-vitro genetic screen of key thiol-disulfide oxidoreductases then completed secondary screens to identify those with mHTT decreasing properties. Our in-vitro experiments identified thioredoxin 1 and thioredoxinrelated transmembrane protein 3 as proteins that decrease soluble mHTT levels in cultured cells. Using a lentiviral mouse model of HD we tested the effect of these proteins in striatum. Both proteins decreased mHTT-induced striatal neuronal atrophy. Findings provide evidence for a role of dysregulated protein-thiol homeostasis in the pathogenesis of HD.

The Role of the Thioredoxin System in Brain Diseases

“…Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder [ 179 , 180 ] caused by a trinucleotide CAG repeats in exon-1 of the huntingtin gene (HTT) on the fourth chromosome (4p16.3) [ 181 ], resulting in the expression of a polyglutamine-expanded mutant Huntington protein (mHTT) at the amino-terminal end of the protein [ 182 ]. The onset of the disease is typically in early to mid-adult life with a range from childhood to advanced age and is defined by an excess of least 39–42 CAG repeats [ 183 , 184 , 185 ].…”

Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5

“…The precise role of TMX3 in cells has not been established, yet. Preliminary studies show a protective function of TMX3 against neuronal atrophy in mice models for Huntington's disease [49], a progressive brain disorder caused by an inherited CAG trinucleotide repeat expansion in the huntingtin (HTT) gene [50]. The molecular basis of this protective effect is unclear, also because HTT is a cytosolic protein and a direct interaction with the functional portion of TMX3 can be ruled out.…”

“…The molecular basis of this protective effect is unclear, also because HTT is a cytosolic protein and a direct interaction with the functional portion of TMX3 can be ruled out. Since it has been shown that the expression of mutated HTT triggers ER stress, an hypothesis is that TMX3 protects cells against neuronal atrophy mitigating the stress situation [49].…”