Abstract
Polyglutamine (polyQ) diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat in the coding region of their respective associated genes. PolyQ diseases mainly display progressive degeneration of the brain and spinal cord. Nine polyQ diseases are known, including Huntington’s disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six forms of spinocerebellar ataxia (SCA). HD is the best characterized polyQ disease. Many studies have reported that transcriptional dysregulation and post-translational disruptions, which may interact with each other, are central features of polyQ diseases. Post-translational modifications, such as the acetylation of histones, are closely associated with the regulation of the transcriptional activity. A number of groups have studied the interactions between the polyQ proteins and transcription factors. Pharmacological drugs or genetic manipulations aimed at correcting the dysregulation have been confirmed to be effective in the treatment of polyQ diseases in many animal and cellular models. For example, histone deaceylase inhibitors have been demonstrated to have beneficial effects in cases of HD, SBMA, DRPLA, and SCA3. In this review, we describe the transcriptional and post-translational dysregulation in polyQ diseases with special focus on HD, and we summarize and comment on potential treatment approaches targeting disruption of transcription and post-translation processes in these diseases.
Highlights
Nine genetic neurodegenerative diseases are caused by the expansion of CAG repeats in seemingly unrelated genes
Transcriptional disruption and post-translational modifications have been well-established as important pathological processes in polyglutamine diseases
Transcriptional disruption may interact with post-translational modifications
Summary
Nine genetic neurodegenerative diseases are caused by the expansion of CAG repeats in seemingly unrelated genes. Several groups have reported that CREB plays an important role in the pathology of HD Choi and his group found that loss of CREB function precedes cell death in a chemical and transgenic mice model of HD. They reported that phosphorylation of CREB in the striatum is potently repressed in the 3-nitropropionic acid (3NP) mouse model, which is often used to model HD pathology (Choi et al, 2009). CREB binding protein, a histone acetyltransferase (HAT), is depleted from its normal nuclear location and is present in polyQ aggregates in HD cell models, HD transgenic mice, and the human HD postmortem brain (Nucifora et al, 2001). Natrium diethyl dithiocarbamate trihydrate (NDDCT) Ethyl pyruvate (EP) Sulforaphane SAHA LBH589
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