How does the CAG triplet expansion lead to neurodegeneration in Huntington's disease?
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Mechanisms of CAG Triplet Expansion Leading to Neurodegeneration in Huntington's Disease
Introduction to Huntington's Disease and CAG Repeat Expansion
Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms. The root cause of HD is the expansion of CAG trinucleotide repeats in the huntingtin (HTT) gene, which leads to the production of an abnormally long polyglutamine tract in the huntingtin protein .
Somatic CAG Repeat Instability and DNA Repair Mechanisms
The instability of CAG repeats varies across different tissues, with the highest instability observed in the brain, correlating with neuropathology. This instability is believed to be driven by secondary DNA structures formed during replication and repair processes. Proteins involved in mismatch repair (MMR) and base excision repair (BER) have been identified as key players in promoting CAG repeat expansion in brain tissues. Additionally, the DNA polymerase θ (Polθ) has been shown to facilitate CAG repeat expansions by extending hairpin primers during base excision repair, contributing to the triplet repeat instability.
Role of FAN1 in Modulating CAG Repeat Expansion
FAN1, a nuclease involved in DNA interstrand cross-link repair, has been identified as a genetic modifier that can influence the progression of HD. Increased expression of FAN1 is associated with delayed onset and slower progression of HD, as it stabilizes the expanded CAG repeats in the HTT gene. This stabilization occurs through a nuclease-independent mechanism, suggesting that FAN1 binds to the expanded CAG repeat DNA and prevents further expansion.
Pathogenic Mechanisms of Mutant Huntingtin Protein
The expanded CAG repeats in the HTT gene result in the production of a mutant huntingtin protein with an elongated polyglutamine tract. This mutant protein undergoes cleavage, producing a toxic N-terminal fragment that misfolds and aggregates within neurons. These aggregates, or inclusions, are found in the nuclei and processes of neurons and are believed to contribute to neurotoxicity through several mechanisms, including caspase activation, transcriptional dysregulation, increased reactive oxygen species production, and inhibition of proteasome activity .
Cellular Stress and Oxidative Damage
Neurons in HD are subjected to oxidative stress and mitochondrial dysfunction, which exacerbate the toxic effects of the mutant huntingtin protein. The dynamic balance between oxidative stress and the antioxidant system is disrupted in HD, leading to neuronal dysfunction and cell death. This oxidative damage further contributes to the instability of CAG repeats and the progression of neurodegeneration.
Clinical Correlations and Genetic Modifiers
The length of the CAG repeat expansion is a significant determinant of the age of onset and severity of HD symptoms. Longer CAG repeats are associated with earlier onset, faster progression, and more severe neurodegeneration. Genetic modifiers, such as FAN1 and other DNA repair proteins, play crucial roles in modulating the disease course by influencing the rate of somatic CAG repeat expansion .
Conclusion
The expansion of CAG repeats in the HTT gene leads to the production of a toxic mutant huntingtin protein, which aggregates and causes neuronal dysfunction and death. The instability of these repeats is driven by DNA repair mechanisms and oxidative stress, with genetic modifiers like FAN1 playing protective roles. Understanding these mechanisms provides insights into potential therapeutic strategies for HD, including targeting DNA repair pathways and stabilizing CAG repeats.
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