scholarly journals Faculty Opinions recommendation of DNA repair in huntington's disease and spinocerebellar ataxias: somatic instability and alternative hypotheses.

2021 ◽  
Author(s):  
Steven Finkbeiner ◽  
Julia Kaye
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Spinocerebellar Ataxias ◽  
Somatic Instability ◽  
Alternative Hypotheses

scholarly journals DNA Repair in Huntington’s Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses

2021 ◽  
Vol 10 (1) ◽  
pp. 165-173 ◽  
Author(s):  
Tamara Maiuri ◽  
Claudia L.K. Hung ◽  
Celeste Suart ◽  
Nola Begeja ◽  
Carlos Barba-Bazan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mismatch Repair ◽  
Dna Damage Repair ◽  
Cross Link ◽  
Somatic Instability ◽  
Damage Repair ◽  
Repair Protein

The use of genome wide association studies (GWAS) in Huntington’s disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

scholarly journals Special Issue: DNA Repair and Somatic Repeat Expansion in Huntington’s Disease

2021 ◽  
Vol 10 (1) ◽  
pp. 3-5
Author(s):  
Lesley Jones ◽  
Vanessa C. Wheeler ◽  
Christopher E. Pearson
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Special Issue

scholarly journals Huntingtin lowering reduces somatic instability at CAG-expanded loci

2020 ◽  
Author(s):  
Sydney R. Coffey ◽  
Marissa Andrew ◽  
Heather Ging ◽  
Joseph Hamilton ◽  
Michael Flower ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Trinucleotide Repeats ◽  
Human Diseases ◽  
Huntingtin Protein ◽  
Somatic Instability ◽  
Human Ipsc ◽  
Knockin Mouse

AbstractExpanded trinucleotide repeats cause many human diseases, including Huntington’s disease (HD). Recent studies indicate that somatic instability of these repeats contributes to pathogenesis in several expansion disorders. We find that lowering huntingtin protein (HTT) levels reduces somatic instability of both the Htt and Atxn2 CAG tracts in knockin mouse models, and the HTT CAG tract in human iPSC-derived neurons, revealing an unexpected role for HTT in regulating somatic instability.

scholarly journals New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Robert S. Lahue
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Model Systems ◽  
Triplet Repeat ◽  
Maximal Effect ◽  
Huntingtin Protein ◽  
Dna Repair Proteins ◽  
Repeat Expansions

Abstract Huntington’s disease (HD) is a fatal, inherited neurodegenerative disease that causes neuronal death, particularly in medium spiny neurons. HD leads to serious and progressive motor, cognitive and psychiatric symptoms. Its genetic basis is an expansion of the CAG triplet repeat in the HTT gene, leading to extra glutamines in the huntingtin protein. HD is one of nine genetic diseases in this polyglutamine (polyQ) category, that also includes a number of inherited spinocerebellar ataxias (SCAs). Traditionally it has been assumed that HD age of onset and disease progression were solely the outcome of age-dependent exposure of neurons to toxic effects of the inherited mutant huntingtin protein. However, recent genome-wide association studies (GWAS) have revealed significant effects of genetic variants outside of HTT. Surprisingly, these variants turn out to be mostly in genes encoding DNA repair factors, suggesting that at least some disease modulation occurs at the level of the HTT DNA itself. These DNA repair proteins are known from model systems to promote ongoing somatic CAG repeat expansions in tissues affected by HD. Thus, for triplet repeats, some DNA repair proteins seem to abandon their normal genoprotective roles and, instead, drive expansions and accelerate disease. One attractive hypothesis—still to be proven rigorously—is that somatic HTT expansions augment the disease burden of the inherited allele. If so, therapeutic approaches that lower levels of huntingtin protein may need blending with additional therapies that reduce levels of somatic CAG repeat expansions to achieve maximal effect.

scholarly journals Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Eshan Khan ◽  
Subodh Kumar Mishra ◽  
Ribhav Mishra ◽  
Amit Mishra ◽  
Amit Kumar
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Small Molecules ◽  
Huntington’S Disease ◽  
Cag Repeats ◽  
Spinocerebellar Ataxias ◽  
Cellular Delivery ◽  
Lead Compounds ◽  
The Common ◽  
Search Approach

AbstractCAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Although there are differences in the pathogenic mechanisms, these diseases share the common cause, i.e., expansion of CAG repeats. The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. Oligonucleotide-based therapeutics are designed earlier with the help of the base pairing rule but are not very promiscuous, considering the nonspecific stimulation of the immune system and the poor cellular delivery. Therefore, small molecules-based therapeutics are preferred for targeting the repeats expansion disorders. Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. The lead compounds showed the specificity towards AA mismatch in biophysical studies including CD, ITC, and NMR spectroscopy and thus aided to forestall the polyQ mediated pathogenicity. Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs.

scholarly journals Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains

2022 ◽  
Author(s):  
Jong-Min Lee ◽  
Yuan Huang ◽  
Michael Orth ◽  
Tammy Gillis ◽  
Jacqueline Siciliano ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Damage ◽  
Association Studies ◽  
Cag Repeat ◽  
Genome Wide Association Studies ◽  
Genetic Modifiers ◽  
Cognitive Domains ◽  
Somatic Instability ◽  
Dna Maintenance

AbstractGenome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document