Transcriptional Dysfunctions as Pathogenic Mechanism of Neurodegenerative Diseases

Summary

Critical steps regulating transcription of DNA into mature messenger RNA include transcription initiation, elongation, termination and pre-mRNA processing. Multiple proteins involved in RNA transcription and pre-mRNA processing can interact with general transcription factors and transcriptional activators, which associate with polymerase at gene promoters. Huntington’s disease, dentatorubralpallidoluysian atrophy and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7) are inherited neurodegenerative diseases caused by expansion of trinucleotide (CAG) repeats encoding polyglutamine (polyQ). Interactions between polyQ tracts and short polyglutamine tracts in ubiquitous transcription factors such as Sp-1, CREB, CBP can sequester basic transcription factors in the cytoplasm affecting transcription initiation. Alternative splicing of mRNA precursors can contribute to the generation of increased protein diversity and determine the subcellular location, molecular interactions, or function of proteins. Neuron-specific proteins involved in RNA splicing and metabolism are affected in several neurological disorders. Defects in RNA processing proteins, such as SMN protein, may lead to the Spinal Muscular Atrophy and aberrant splicing of glutamate receptors is linked to the pathology of Amyotrophic Lateral Sclerosis. Fragile X Mental Retardation Protein (FMRP) is mRNA binding protein and may regulate translation of dendrically localised mRNA influencing local protein synthesis and affecting synaptic structure and plasticity.