Gene Alterations Induced by Glutamine (Q) Encoding CAG Repeats Associated with Neurodegeneration

Abstract

Several studies have been reported linking the role of polyglutamine (polyQ) disease-associated proteins with altered gene regulation induced by an unstable trinucleotide (CAG) repeat. Owing to their dynamic nature of expansion, these DNA repeats form secondary structures interfering with the normal cellular mechanisms like replication and transcription and, thereby, have become the underlying cause of numerous neurodegenerative disorders involving mental retardation and/or muscular or neuronal degeneration. Despite the widespread expression of the disease-causing protein, specific subsets of neurons are susceptible to specific patterns of inheritance and clinical symptoms. Although this cell-type selectivity is still elusive and less understood, it has been found that aberrant transcriptional regulation is one of the primary causes of polyQ diseases where the functions of histone-modifying complexes are disrupted. Besides, epigenetic modifications play a critical role in the pathogenesis of these diseases. In this chapter, we will be delving into how these polyQ repeats induce the self-assembly and aggregation of altered carrier proteins based on gene alterations, causing neuronal toxicity and cellular deaths. Besides, genomic instability in CAG repeats due to altered chromatin-related enzymes will be highlighted, along with epigenetic changes present in many polyQ disorders. Understanding the underlying molecular mechanisms in the root cause of these disorders will culminate in identifying therapeutic approaches for the treatment of these neurodegenerative disorders.