Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases

doi:10.1016/S1471-4914(01)02179-7

Trends in Molecular Medicine

Volume 7, Issue 11, 1 November 2001, Pages 479-482

https://doi.org/10.1016/S1471-4914(01)02179-7 Get rights and content

Abstract

The expansion in the identification of repeat expansion neurodegenerative diseases is leading to an increase in our understanding of their molecular mechanisms. Neuronal cell death is likely to be caused mainly by genetic gain-of-function mechanisms, with possible contribution from loss-of-function mechanisms as well. Postulated mechanisms involve abnormalities of protein folding, chaperone interactions, alterations in gene transcription, loss of neurotrophic support, and involvement of signal transduction pathways. Understanding the pathogenesis in these diseases is leading to the development of therapeutic strategies.

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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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.
Polyglutamine (polyQ) diseases, including Huntington’s disease, result from the aggregation of an abnormally expanded polyQ repeat in the affected protein. The length of the polyQ repeat is essential for the disease’s onset; however, the molecular mechanism of polyQ aggregation is still poorly understood. Controlled conditions and initiation of the aggregation process are prerequisites for the detection of transient intermediate states. We present an attenuated total reflection Fourier-transform infrared spectroscopic approach combined with protein immobilization to study polyQ aggregation dependent on the polyQ length. PolyQ proteins were engineered mimicking the mammalian N-terminus fragment of the Huntingtin protein and containing a polyQ sequence with the number of glutamines below (Q11), close to (Q38), and above (Q56) the disease threshold. A monolayer of the polyQ construct was chemically immobilized on the internal reflection element of the attenuated total reflection cell, and the aggregation was initiated via enzymatic cleavage. Structural changes of the polyQ sequence were monitored by time-resolved infrared difference spectroscopy. We observed faster aggregation kinetics for the longer sequences, and furthermore, we could distinguish β-structured intermediates for the different constructs, allowing us to propose aggregation mechanisms dependent on the repeat length. Q11 forms a β-structured aggregate by intermolecular interaction of stretched monomers, whereas Q38 and Q56 undergo conformational changes to various β-structured intermediates, including intramolecular β-sheets.
Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity
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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.
Polyglutamine diseases are a family of inherited neurodegenerative diseases caused by the expansion of CAG repeats within the coding region of target genes. Still the mechanism(s) by which polyglutamine proteins are ubiquitinated and degraded remains obscure. Here, for the first time, we demonstrate that Mahogunin 21 ring finger 1 E3 ubiquitin protein ligase is depleted in cells that express expanded-polyglutamine proteins. MGRN1 co-immunoprecipitates with expanded-polyglutamine huntingtin and ataxin-3 proteins. Furthermore, we show that MGRN1 is predominantly colocalized and recruits with polyglutamine aggregates in both cellular and transgenic mouse models. Finally, we demonstrate that the partial depletion of MGRN1 increases the rate of aggregate formation and cell death, whereas the overexpression of MGRN1 reduces the frequency of aggregate formation and provides cytoprotection against polyglutamine-induced proteotoxicity. These observations suggest that stimulating the activity of MGRN1 ubiquitin ligase might be a potential therapeutic target to eliminate the cytotoxic threat in polyglutamine diseases.
Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway
2012, Neurobiology of Disease
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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).
Expansion of polyglutamine repeats is the cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease (HD). It is widely accepted that deregulation of the transcriptional coactivator CBP by expanded huntingtin (htt) plays an important role in HD molecular pathogenesis. In this study, we report on a novel target of expanded polyglutamine stretches, the transcriptional coactivator Jun activation domain-binding protein 1 (Jab1), which shares DNA-sequence-specific transcription factor targets with CBP. Jab1 also plays a major role in the degradation of the cyclin-dependent-kinase inhibitor and putative transcription cofactor p27(Kip1). We found that Jab1 accumulates in aggregates when co-expressed with either expanded polyglutamine stretches or N-terminal fragments of mutant htt. In addition, the coactivator function of Jab1 was suppressed both by aggregated expanded polyglutamine solely and by mutant htt. Inhibition by mutant htt even preceded the appearance of microscopic aggregation. In an exon 1 HD cell model, we found that endogenous Jab1 could be recruited into aggregates and that this was accompanied by the accumulation of p27(Kip1). Accumulation of p27(Kip1) was also found in brains derived from HD patients. The repression of Jab1 by various mechanisms coupled with an increase of p27(Kip1) at late stages may have important transcriptional effects. In addition, the interference with the Jab1-p27(Kip1) pathway may contribute to the observed lower incidence of cancer in HD patients and may also be relevant for the understanding of the molecular pathogenesis of polyglutamine disorders in general.
The endoplasmic reticulum and neurological diseases
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Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntington's disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.
Biologic models of neurodegenerative disorders
2008, Handbook of Clinical Neurology
In human neurodegenerative disorders, genetic mutations that are identified in familiar forms of disease have served as a starting point for recapitulating the underlying pathological processes in biologic models. The central rationale supporting the development of biologic models is that they enable researchers to apply powerful experimental tools to understand the fundamental biology of neurodegenerative disease. The chapter describes how the mutant forms of genes that are associated with pathological phenotypes have been cloned into transgenic mouse, fly, and worm models. The chapter elucidates that utilizing a mutant gene that has only been shown to be associated with a small fraction of disease cases may yield an incomplete or misleading model. Despite these potential pitfalls, most models of neurodegenerative disease recapitulate some aspects of the disease and enhance our understanding of the disorder. The chapter further explains that the bulk of the evidence supporting the use of these models currently favors disturbances in basic cellular processes that are tightly conserved between vertebrate and invertebrate species.

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Trends in Molecular Medicine

Research updateExpansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases

Abstract

Section snippets

SCA17 and glutamine expansion in TBP

Toxic gain-of-function hypothesis

Why neurons?

A loss-of-function model

Non-glutamine expansions

Conclusions

Trends Genet.

Am. J. Hum. Genet.

Neuron

Cell

Neuron

Cell

Trends Mol. Med

Am. J. Hum. Genet.

SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein

Hum. Mol. Genet.

Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel

Nat. Genet.

Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology

Proc. Natl. Acad. Sci. U. S. A.

Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans

Proc. Natl. Acad. Sci. U. S. A.

Research update
Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases

Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α_1A-voltage-dependent calcium channel