Polyglutamine Expansion in Huntingtin and Mechanism of DNA Damage Repair Defects in Huntington’s Disease

Abstract

Emerging evidence suggests that DNA repair deficiency and genome instability may be the impending signs of many neurological diseases. Genome-wide association (GWAS) studies have established a strong correlation between genes that play a role in DNA damage repair and many neurodegenerative diseases, including Huntington’s disease (HD), and several other trinucleotides repeat expansion-related hereditary ataxias. Recently, many reports have documented a significant role played by the DNA repair processes in aging and in modifying many neurodegenerative diseases, early during their progression. Studies from our lab and others have now begun to understand the mechanisms that cause defective DNA repair in HD and surprisingly, many proteins that have a strong link to known neurodegenerative diseases seem to be important players in these cellular pathways. Mutations in huntingtin (HTT) gene that lead to polyglutamine repeat expansion at the N-terminal of HTT protein has been shown to disrupt transcription-coupled DNA repair process, a specialized DNA repair process associated with transcription. Due to the recent progress made in understanding the mechanisms of DNA repair in relation to HD, in this review, we will mainly focus on the mechanisms by which the wild-type huntingtin (HTT) protein helps in DNA repair during transcription, and the how polyglutamine expansions in HTT impedes this process in HD. Further studies that identify new players in DNA repair will help in our understanding of this process in neurons. Furthermore, it should help us understand how various DNA repair mechanism(s) coordinate to maintain the normal physiology of neurons, and provide insights for the development of novel drugs at prodromal stages of these neurodegenerative diseases.

Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets

“…One of the top statistically significantly enriched pathways was DNA signaling (DNA replication pathway, double-stand break repair, G1/S transition). This fits with numerous studies in the field suggesting an increase in DNA damage in HD, defects in DNA repair mechanisms and a multitude of genes that enhance or prevent CAG expansion modifying the age of onset of HD (129, 130). We identified the MCM proteins 2–7 as a top dysregulated pathway.…”

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

“…Finally, some ASOs do not target mHtt, but genes involved in the DNA damage response pathway because defective repair of double-streak breaks in the DNA, the most lethal forms of DNA injury, have been found in postmortem examinations of brain cells in HD patients [ 165 ]. Mutant Htt impairs the non-homologous end-joining (NHEJ)-mediated DNA DSB repair mechanism in neurons [ 166 , 167 ], suggesting that alterations of the DNA repair mechanism could have important contributions to the prominent cell loss. Targeting the mutS homolog 3 (MSH3) with TTX-3360 with ASOs, developed by Triplet Therapeutics, proved safe and efficient in mouse models of HD [ 153 ].…”

The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington’s Disease

“…Current HD treatment focuses mainly on managing chorea and psychiatric and cognitive deficits. − Tetrabenazine ( 1 ) and deutetrabenazine ( 2 ) are the two Food and Drug Administration (FDA) approved drugs for managing chorea. , Off-label use of drugs for chorea and HD-related psychosis is also widespread . Other neurobehavioral manifestations of HD, such as depression, agitation, and anxiety, are treated with benzodiazepines and selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (SSRIs or SNRIs).…”

“…Huntington’s disease (HD) is a rare hereditary disease with a global frequency of 2.7 cases per 100 000 individuals, with Europe, Australia, and North America having the greatest prevalence (5.7/100 000) and Asian populations having the lowest (0.4/100 000). , Though there are certain juvenile forms of HD with the disease onset prior to 20 years of age, they are uncommon, accounting for approximately 5% of all cases. , While adults have typical HD symptoms such as movement disorder or chorea, juvenile HD patients experience symptoms such as mental disturbance and stiffness rather than chorea. − …”

“…HD is a heterogeneous disease, and symptoms vary from person to person. However, the typical symptoms include choreatic involuntary movements and motor deficits, mild to severe cognitive deterioration, and behavioral and psychiatric anomalies. − These symptoms may not appear at the onset of the disease and they commonly vary across the patient and afflicted family members; nonetheless, the symptoms worsen with disease progression. − These symptoms often appear in adults (in the middle-age group) with psychiatric and cognitive deficits; however, examples of juvenile onset (age group as young as two years) have also been reported. − Early onset HD motor coordination abnormalities in adults include choreiform movements with gait disturbances, while motor deficits, such as bradykinesia and stiffness, typically appear later in the disease progression. − Cognitive impairment begins with modest disruptions and progresses to observable cognitive deterioration. − Furthermore, HD patients suffer from planning routine activities, loss of mental flexibility, and frequent failure to make minor modifications. − Finally, HD patients may exhibit frequent despair, extreme mood swings, anxiety, irritability, apathy, impulsivity, and social isolation. − Though HD is a complex disease, due to the subtle molecular alterations that occur prior to clinical onset, it offers a window of opportunity for viable and effective therapeutic approaches.…”