Genetic Modifiers of CAG.CTG Repeat Instability in Huntington's Disease Mouse Models

Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder whose characterstics were first described by George Huntington in 1872. Several decades later, in 1993, the mutation behind this disease was found to be an unstable expanded CAG repeat within exon 1 of the HTT gene localized on the short arm of chromosome 4. The majority of HD patients carry more than 40 CAG repeats, which become unstable and usually increase in size in successive generations and in tissues. In order to dissect the molecular mechanisms underlying CAG repeat instability, several HD mouse models have been created in the 1990s. Significant data have revealed that the absence of proteins from the mismatch repair (MMR) or the base and nucleotide excision repair decreased the pathogenic expansion-biased somatic mosaicism and/or intergenerational expansions. Some polymorphic variants of MMR genes have also been associated with reduced somatic expansions. Since expansionbiased somatic mosaicism likely contributes to disease manifestations, these results suggest that genetic modifiers of instability may also affect disease severity. In this chapter, we provide an overview of the data recently published about DNA instability; the roles of genetic modifiers of trinucleotide repeat dynamics in mouse models; and the possible therapeutic interventions.

Neurodegenerative Diseases – Is Metabolic Deficiency the Root Cause?

“…In aging, larger numbers of reactive astrocytes (A1) are observed in CA1 and striatal regions that, in turn, induce neuroinflammation and vulnerability in pyramidal neurons and MSNs of CA1 and striatal regions, respectively (Clarke et al, 2018). Studies have shown age-dependent increase in the β-amyloid, α-synuclein, SOD1, and Htt protein aggregation (Kennedy, 2000;Ishiguro et al, 2001;Lee et al, 2011;Tomé and Dandelot, 2017;Medinas et al, 2018Medinas et al, , 2019. Because of the energy crisis, this type of aggregation leads to enormous stress in the specific neuronal classes.…”