Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets

Costa, Marta; Pereira-Sousa, Joana

doi:10.1007/s00018-022-04280-8

“…36 Table 1. Polyglutamine (polyQ) repeat expansion diseases 1,22,25,[36][37][38][39][40][41][42][43][44][45]…”

Section: Polyq Diseases Definition and Common Features Of Polyq Disea...mentioning

confidence: 99%

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Tenchov,

Sasso,

Zhou

2024

Preprint

0

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.

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“…While somatic hypermutation itself is not the cause of polyQ diseases, the mechanisms by which CAG repeats expand somatically in affected individuals’ cells are of great interest. Understanding these mechanisms could potentially lead to therapeutic approaches that target the process of repeat expansion and thereby mitigate the progression of polyQ diseases. , …”

Section: Polyq Diseasesmentioning

confidence: 99%

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Tenchov,

Sasso,

Zhou

2024

ACS Chem. Neurosci.

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding proteins with abnormally expanded polyglutamine tract. A total of nine polyQ disorders have been identified, including Huntington's disease, six spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). The diseases of this class are each considered rare, yet polyQ diseases constitute the largest group of monogenic neurodegenerative disorders. While each subtype of polyQ diseases has its own causative gene, certain pathologic molecular attributes have been implicated in virtually all of the polyQ diseases, including protein aggregation, proteolytic cleavage, neuronal dysfunction, transcription dysregulation, autophagy impairment, and mitochondrial dysfunction. Although animal models of polyQ disease are available helping to understand their pathogenesis and access disease-modifying therapies, there is neither a cure nor prevention for these diseases, with only symptomatic treatments available. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in the class of polyQ diseases. We examine the publication landscape in the area in effort to provide insights into current knowledge advances and developments. We review the most discussed concepts and assess the strategies to combat these diseases. Finally, we inspect clinical applications of products against polyQ diseases with their development pipelines. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding the class of polyQ diseases, to outline challenges, and evaluate growth opportunities to further efforts in combating the diseases.

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“…In humans, nine proteins with polymorphic polyQ repeats–including AR–have pathological implications when their repeat lengths are out of the physiological range ( 47 , 48 ). These proteins have been the subject of various studies to shed light on the molecular mechanism of the relationships between the length and biological effect ( Table 1A ).…”

Section: Structure Function and Disease Relevance Of The Androgen Rec...mentioning

confidence: 99%

The evolution and polymorphism of mono-amino acid repeats in androgen receptor and their regulatory role in health and disease

Mészáros

¹

,

Ahmed²,

Russo³

et al. 2022

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Androgen receptor (AR) is a key member of nuclear hormone receptors with the longest intrinsically disordered N-terminal domain (NTD) in its protein family. There are four mono-amino acid repeats (polyQ1, polyQ2, polyG, and polyP) located within its NTD, of which two are polymorphic (polyQ1 and polyG). The length of both polymorphic repeats shows clinically important correlations with disease, especially with cancer and neurodegenerative diseases, as shorter and longer alleles exhibit significant differences in expression, activity and solubility. Importantly, AR has also been shown to undergo condensation in the nucleus by liquid-liquid phase separation, a process highly sensitive to protein solubility and concentration. Nonetheless, in prostate cancer cells, AR variants also partition into transcriptional condensates, which have been shown to alter the expression of target gene products. In this review, we summarize current knowledge on the link between AR repeat polymorphisms and cancer types, including mechanistic explanations and models comprising the relationship between condensate formation, polyQ1 length and transcriptional activity. Moreover, we outline the evolutionary paths of these recently evolved amino acid repeats across mammalian species, and discuss new research directions with potential breakthroughs and controversies in the literature.

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Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets

Cited by 8 publications

References 171 publications

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

Polyglutamine (PolyQ) Diseases: Navigating the Landscape of Neurodegeneration

The evolution and polymorphism of mono-amino acid repeats in androgen receptor and their regulatory role in health and disease

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