Search results for "polyglutamine"

Between Interactions and Aggregates: The PolyQ Balance

2021

Abstract Polyglutamine regions (polyQ) are highly abundant consecutive runs of glutamine residues. They have been generally studied in relation to the so-called polyQ-associated diseases, characterized by protein aggregation caused by the expansion of the polyglutamine tract via a CAG-slippage mechanism. However, more than 4800 human proteins contain a polyQ, and only 9 of these regions are known to be associated with disease. Computational sequence studies and experimental structure determinations are completing a more interesting picture in which polyQ emerge as a motif for modulation of protein-protein interactions. But long polyQ regions may lead to an excess of interactions, and produc…

Polyglutamine toxicity induces rod photoreceptor division, morphological transformation or death in Spinocerebellar ataxia 7 mouse retina

2010

In neurodegenerative disorders caused by polyglutamine (polyQ) expansion, polyQ toxicity is thought to trigger a linear cascade of successive degenerative events leading to neuronal death. To understand how neurons cope with polyQ toxicity, we studied a Spinocerebellar ataxia 7 (SCA7) mouse which expresses polyQ-expanded ATXN7 only in rod photoreceptors. We show that in response to polyQ toxicity, SCA7 rods go through a range of radically different cell fates, including apoptotic and non-apoptotic cell death, cell migration, morphological transformation into a round cell or, most remarkably, cell division. The temporal profile of retinal remodeling indicates that some degenerative pathways …

Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery

2020

Spinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are somehow linked to neuronal death. However, owing to lack of a suitable cellular model, the downstream consequences of IIB formation are yet to be resolved. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1 and characterize IIB effects. Using an inducible Sleeping Beauty transposon system, we overexpressed the ATXN1(Q82) gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects caused by the expr…

Avian Clock gene polymorphism: evidence for a latitudinal cline in allele frequencies

2007

In comparison with most animal behaviours, circadian rhythms have a well-characterized molecular genetic basis. Detailed studies of circadian clock genes in 'model' organisms provide a foundation for interpreting the functional and evolutionary significance of polymorphic circadian clock genes found within free-living animal populations. Here, we describe allelic variation in a region of the avian Clock orthologue which encodes a functionally significant polyglutamine repeat (ClkpolyQcds), within free-living populations of two passerine birds, the migratory bluethroat (Luscinia svecica) and the predominantly nonmigratory blue tit (Cyanistes caeruleus). Multiple ClkpolyQcds alleles were foun…

Differences in activation of MAP kinases and variability in the polyglutamine tract of Slt2 in clinical and non-clinical isolates of Saccharomyces ce…

2010

The concept of Saccharomyces cerevisiae as an emerging opportunistic pathogen is relatively new and it is due to an increasing number of human infections during the past 20 years. There are still few studies addressing the mechanisms of infection of this yeast species. Moreover, little is known about how S. cerevisiae cells sense and respond to the harsh conditions imposed by the host, and whether this response is different between clinical isolates and non-pathogenic strains. In this regard, mitogen-activated protein kinase (MAPK) pathways constitute one of the major mechanisms for controlling transcriptional responses and, in some cases, virulence in fungi. Here we show differences among …

Deregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease.

2019

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Here, we describe the analysis of proteins that preferentially bind mutant HTT RNA using a mass spectrometry approach. We show that (I) the majority of proteins captured by mutant…

UNDERSTANDING THE RELATIONSHIP BETWEEN NORMAL FUNCTION AND ABERRANT AGGREGATION: THE CASE OF ATAXIN-3

2020

Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis.

2012

ABSTRACT Objective: Recent evidence suggests that intermediate-length polyglutamine (PolyQ) expansions in the ataxin-2 ( ATXN-2 ) gene are a risk factor for amyotrophic lateral sclerosis (ALS). This work was undertaken with the aim to investigate the frequency of ataxin-1 ( ATXN-1 ) and ATXN-2 PolyQ expansions in a cohort of patients with sporadic ALS (sALS) and patients with familial ALS (fALS) from southern Italy. Methods: We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders. Results: We found significantly higher intermediate PolyQ expansions ≥32 for ATXN-1 alleles an…