Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets

Kumar, Raj

doi:10.1002/iub.1088

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…CAG repeat may be involved in the pathogenesis of some neurodegenerative diseases [ 100 ]. However, the most studied and robust relationship is the one with spinal-bulbar muscular atrophy (SBMA).…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action

Tirabassi

Cignarelli

Perrini

et al. 2015

International Journal of Endocrinology

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In the last decade, ample evidence has demonstrated the growing importance of androgen receptor (AR) CAG repeat polymorphism in andrology. This genetic parameter is able to condition the peripheral effects of testosterone and therefore to influence male sexual function and fertility, cardiovascular risk, body composition, bone metabolism, the risk of prostate and testicular cancer, the psychiatric status, and the onset of neurodegenerative disorders. In this review, we extensively discuss the literature data and identify a role for AR CAG repeat polymorphism in conditioning the systemic testosterone effects. In particular, our main purpose was to provide an updated text able to shed light on the many and often contradictory findings reporting an influence of CAG repeat polymorphism on the targets of testosterone action.

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Section: Neurodegenerative Disordersmentioning

confidence: 99%

Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action

Tirabassi

Cignarelli

Perrini

et al. 2015

International Journal of Endocrinology

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“…Other small molecules structurally related to trehalose may have the potential to revert ARpolyQ accumulation and aggregation. Trehalose is considered a natural osmolyte and/or "chemical chaperone" (Kumar, 2012). Its advantage as a small molecule, which is shared by other osmolytes, is that it can cross the blood-brain barrier with high efficiency.…”

Section: B) Activation Of Autophagymentioning

confidence: 99%

The Role of the Protein Quality Control System in SBMA

et al. 2015

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Spinal and Bulbar Muscular Atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon-1 on the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In these review we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperons and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species.

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“…Furthermore, osmolytes have also been observed to modulate conformational changes within Hsp90 [59], which is part of the chaperone machinery complexed with the unliganded AR. Naturally occurring osmolytes have an added advantage in that they can easily cross the blood–brain barrier thus serve as a potential therapeutic tools [60]. …”

Section: Future Research Focus and Its Impact On Development Of Novel Tmentioning

confidence: 99%

Trinucleotide Repeats and Protein Folding and Disease: the Perspective From Studies With the Androgen Receptor

Orafidiya

McEwan

2015

Future Sci. OA

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The androgen receptor (AR), a ligand activated transcription factor plays a number of roles in reproduction, homeostasis and pathogenesis of disease. It has two major polymorphic sequences; a polyglutamine and a polyglycine repeat that determine the length of the protein and influence receptor folding, structure and function. Here, we review the role the folding of the AR plays in the pathogenesis of spinal-bulbar muscular atrophy (SBMA), a neuromuscular degenerative disease arising from expansion of the polyglutamine repeat. We discuss current management for SBMA patients and how research on AR structure function may lead to future drug treatments.

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Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets

Cited by 8 publications

References 47 publications

Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action

Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action

The Role of the Protein Quality Control System in SBMA

Trinucleotide Repeats and Protein Folding and Disease: the Perspective From Studies With the Androgen Receptor

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