Det finns två olika forskningslinjer syftande till att bota sjukdomen.

1. Den ena är  siRNA som går ut på att “släcka ut” den muterade genen. Denna gren är även applicerbar för andra sjukdomar, såsom vissa andra SCA-sjukdomar.

2. Den andra grenen går ut på blockad av protein misfolding.

Nedan framgår en artikel för vardera forskningsgren.


1. Allele-specific silencing of dominant disease genes.

Miller VM, Xia H, Marrs GL, Gouvion CM, Lee G, Davidson BL, Paulson HL.

Department of Neurology, Graduate Program in Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.

Small interfering RNA (siRNA) holds therapeutic promise for silencing dominantly acting disease genes, particularly if mutant alleles can be targeted selectively. In mammalian cell models we demonstrate that allele-specific silencing of disease genes with siRNA can be achieved by targeting either a linked single-nucleotide polymorphism (SNP) or the disease mutation directly. For a polyglutamine neurodegenerative disorder in which we first determined that selective targeting of the disease-causing CAG repeat is not possible, we took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant Machado-Joseph disease/spinocerebellar ataxia type 3 allele while sparing expression of the WT allele. Allele-specific suppression was accomplished with all three approaches currently used to deliver siRNA: in vitro-synthesized duplexes as well as plasmid and viral expression of short hairpin RNA. We further optimized siRNA to specifically target a missense Tau mutation, V337M, that causes frontotemporal dementia. These studies establish that siRNA can be engineered to silence disease genes differing by a single nucleotide and highlight a key role for SNPs in extending the utility of siRNA in dominantly inherited disorders.

PMID: 12782788 [PubMed – indexed for MEDLINE]

Neurobiol Dis. 2005 Oct;20(1):170-8.
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2. Ectoine alters subcellular localization of inclusions and reduces apoptotic cell death induced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch.

Furusho K, Yoshizawa T, Shoji S.

Department of Neurology, Institute of Clinical Medicine, Graduate School of Comprehensive Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.

Protein misfolding is considered a key event in the pathogenesis of polyglutamine disease such as Machado-Joseph disease (MJD). Overexpression of chaperone proteins and the application of chemical chaperones are reported to suppress polyglutamine induced cytotoxicity in vitro and in vivo. The effects of compatible solutes, which are osmoprotectants in bacteria and possess the action in stabilizing proteins under stress, have not, to our knowledge, been studied. We explored the protective effects of the compatible solutes ectoine, hydroxyectoine, and betaine on apoptotic cell death produced by the truncated MJD gene product with an expanded polyglutamine tract in cultured neuro2a cells. Ectoine, but not hydroxyectoine or betaine, decreased large cytoplasmic inclusions and increased the frequency of nuclear inclusions. Immunoblot analysis showed that ectoine reduced the total amount of aggregates. Despite the presence of nuclear inclusions, apoptotic features were less frequently observed after ectoine application. Our findings suggest that ectoine, a natural osmoprotectant in bacteria, may function as a novel molecule protecting cells from polyglutamine-induced toxicity.

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