Polyglutamine (PolyQ) Diseases: Genetics to Treatments

Abstract

The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosineadenine-guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.

New Insight into Alzheimer’s Disease via Caspase 3-cleaved Tau: Pathogenic Role in Tau Oligomer Formation and Memory Deficits

“…Compared to normal tau, genetic mutation in or post-translational modification of tau facilitates the formation of tau aggregates. Similar intracellular protein oligomer and aggregate conformers found in other neurodegenerative diseases, such as mutant Huntingtin in Huntington's disease [9,10], Spinocerebellar ataxia type 1 (SCA) in spinocerebellar ataxia [11], alpha-synuclein in Parkinson's disease [12], and TAR DNAbinding protein-43 (TDP-43) in amyotrophic lateral sclerosis [13] are also thought to induce the respective diseases [14]. Therefore, it is important to study the tau species between oligomers and aggregates found in Alzheimer's disease, with particular attention to their role in memory impairment and the loss of synaptic function.…”

Variation and evolution of the glutamine-rich repeat region of Drosophila Argonaute-2

“…Although genetic studies have elucidated the function of Ago2 in D. melanogaster, the role of the GRR is still unknown. In other proteins, long polyglutamine-rich regions have been implicated in increased protein adhesion and protein complex formation, and underlie numerous human diseases (reviewed in Fan et al 2014). However these are generally long contiguous tracts of glutamine residues, in contrast to the short complex repeat units observed in the Ago2 GRR.…”

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…There is much debate as to the exact role neuronal nuclear inclusions plays in pathogenesis, as researchers are still unable to determine whether the aggregates directly induce neurodegeneration or if the presence of misfolded proteins and oligomeric intermediates are to blame [7,8,[222][223][224]. However, the prevention or reversal of neuronal nuclear inclusions still remains one of the most attractive avenues for therapeutic treatment [225].…”

“…These six diseases (SCA1, 2,3,6,7,17) are caused by an expansion of a CAG repeating sequencing in the coding region of six independent genes. All six diseases present with common ataxic symptoms, however, there is still a large degree of phenotypic variation, from the rapid and early progression of SCA7, to the more slowly progressive, milder form of SCA6.…”

“…Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option.…”