Transcriptional up-regulation and its impact on poly(Q) disorders

The polyglutamine [poly(Q)] disorders are a class of late-onset genetic disorders those are manifested by progressive loss of neurons in the human brain, leading to cognitive and behavioural impairments. Expansion of CAG trinucleotide repeats in the coding region of the certain genes translate into long poly(Q) tract in the corresponding protein, and consequently, cause gain of function in mutant protein. Underlying the basic cause to neurodegeneration, several mechanisms have been proposed to elucidate the enigma behind the pathology of poly(Q) disorders. However, almost in all instances, till now the exact mechanism(s) of disease pathogenesis remain elusive. In recent years, impairment of cellular transcriptional machinery either due to mutation in the putative poly(Q) genes or sequestration of several nuclear transcription factors has emerged as the main attention for disease pathogenesis. An increased body of evidences suggest that defects in global chromatin structures due to limitation of nuclear transcription factors and chromatin remodelling proteins could be the basic foundation to the poly(Q) pathology. Therefore, balancing the rate of global transcription and compensation of the various survival factors which are otherwise compromised during early stages of disease onset could provide development of some novel therapeutic strategies against these fatal neurodegenerative disorders.