Trends in Molecular Medicine
Research updateExpansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases
Section snippets
SCA17 and glutamine expansion in TBP
The recent report that an expansion in the gene encoding the TATA binding protein (TBP) causes a form of SCA (Ref. 2) brings the number of dominant SCAs with distinct genetic loci to 17 (Table 1), with others rumored to be on the way. SCA17 is representative of the diseases involving expansion of polyglutamine. It is characterized by prominent spinocerebellar degeneration, but also basal ganglia, thalamic and cortical degeneration. The normal range of the TBP repeat is 25–42 glutamines, whereas
Toxic gain-of-function hypothesis
The major pathogenic mechanism of these diseases is believed to arise from a genetic gain of function relating to abnormal conformation of the elongated polyglutamine tracts. Other than the polyglutamine repeats, the disease proteins are unrelated to each other. Nevertheless, they all cause neuronal degeneration, in overlapping, although distinct, regions of the brain 4. All the polyglutamine expansion diseases are dominantly inherited [spinal and bulbar muscular atrophy (SBMA) is X-linked,
Why neurons?
Why do the polyglutamine disorders selectively affect neurons? This remains a major unanswered question. Part of the explanation might lie with unique aspects of polyglutamine toxicity. For example, some of the transcription factors sequestered in polyglutamine aggregates or some of the proteosome subunits that are vulnerable to deactivation by polyglutamine might be specifically expressed in neurons. Less specific factors, thought to play a role in neurodegeneration from many causes, could
A loss-of-function model
Although a gain-of-function best fits the genetic evidence, and most models of the polyglutamine diseases, it is possible that a loss of the normal functions of proteins with an expanded polyglutamine also contributes to disease pathogenesis. For example, polyglutamine expansions might reduce the normal capacity of huntingtin to stimulate BDNF, a neuronal growth factor with neuroprotective properties 19. Whether this finding will be replicated in other systems and other diseases remains to be
Non-glutamine expansions
Curiously, several of the SCAs, phenotypically similar to the others, are associated with expansions that do not encode glutamine. SCA8 involves a CTG expansion in a 5′ exon of an apparently untranslated transcript that could function as an antisense regulator of a gene encoded on the opposite DNA strand 20. The high rate of nonpenetrance of the SCA8 mutation within affected families, and the frequency with which expansions are found in the normal population, has complicated the molecular and
Conclusions
The rapid development of models for the polyglutamine diseases has led to optimism that therapeutic approaches can be devised. Academic–industrial collaboration towards that end has already emerged 25. Recently, the National Institute of Neurological Disorders and Stroke, in conjunction with several private foundations, has launched an initiative to fund individual investigators to screen a collection of FDA approved compounds for efficacy against models of neurodegenerative diseases. Nearly
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Insights into the Aggregation Mechanism of PolyQ Proteins with Different Glutamine Repeat Lengths
2018, Biophysical JournalCitation Excerpt :Over the last decades, many research studies focused on understanding the development of the genetically inherited neurodegenerative disorders called “polyQ diseases.” PolyQ diseases include Huntington’s, Kennedy’s disease (spinal and bulbar muscular atrophy), several forms of spinocerebellar ataxia, and dentatorubral-pallidoluysian atrophy (1–3). These diseases are accompanied by the progressive death of neurons.
Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity
2014, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Numerous neurodegenerative diseases are caused by trinucleotide repeats, and polyglutamine diseases are caused by a (CAG)n expansion within the coding region of the responsible gene. Polyglutamine diseases such as Huntington's disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7 and 17) and X-linked spinal bulbar muscular atrophy (SBMA) are most likely caused by the neuronal dysfunction or neuronal cell death that results as the lengths of the glutamine stretches/repeats increase; early disease onset and the accumulation of intracellular aggregates are strongly linked with increased polyglutamine tract length [4–6]. The question of whether the molecular pathology that underlies polyglutamine disease is caused by a gain or a loss of function is controversial.
Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway
2012, Neurobiology of DiseaseCitation Excerpt :Expanded polyglutamine causes nine inherited neurodegenerative disorders, including Huntington's disease (HD), spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and six spinocerebellar ataxias (Margolis and Ross, 2001).
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