Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease

Chua, Jason P.; Reddy, Satya L.; Zhang, Yu; Giorgetti, E.; Montie, Heather L.; Mukherjee, Sarmistha; Higgins, John; McEachin, Richard C.; Robins, Diane M.; Merry, Diane E.; Iñiguez‐Lluhí, Jorge A.; Lieberman, Andrew P.

doi:10.1172/jci73214

Cited by 46 publications

(56 citation statements)

References 68 publications

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“…SBMA, is whether intracellular inclusions of disease-associated protein are directly cytotoxic (11). For SBMA, it has been suggested that SUMOylation reduces aggregation of polyQ AR; however, Chua et al saw no difference in aggregation between AR113Q and AR113Q-KRKR, implying, at least in this model, that SUMOylation does not regulate protein aggregation (9). A logical extrapolation based on this observation is that polyQ AR inclusions are not responsible for any of the aspects of the disease that can be rescued by AR113Q-KRKR and therefore AR aggregation is not responsible for its loss of function in SBMA.…”

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confidence: 86%

“…Specifically, survival rates and exercise capacity were severely reduced in AR113Q mice, whereas these parameters were indistinguishable in AR113Q-KRKR mice compared with WT mice (9). Importantly, survival and exercise capacity in castrated AR113Q-KRKR males were similar to AR11Q, demonstrating that amelioration of these symptoms requires the presence of androgen.…”

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confidence: 89%

“…generated a transgenic knockin mouse to dissect the relative contributions of toxic gain of function and loss of function of the polyQ AR in SBMA (9). Using this model, Chua and colleagues demonstrate that increasing the intrinsic transcriptional activation capacity of the AR by inhibiting SUMOylation ameliorates some of the deleterious effects of polyQ AR-mediated disease.…”

Section: Perspectives: Interesting Basic Science And/or a Viable Treamentioning

confidence: 99%

“…In this issue, Chua et al report on their development of knockin mice in which the native Ar locus was replaced with one encoding either a polyQ AR (AR113Q) or a nonSUMOylatable polyQ AR in which lysine residues 385 and 518 were mutated to arginine (AR113Q-KRKR) (9). Because SUMOylation inhibits AR transcriptional activity, it was predicted that the AR113Q-KRKR mutant would rescue some of the transcription deficiencies caused by AR113Q.…”

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confidence: 99%

“…Chua et al demonstrated that, compared with mice harboring the AR113Q mutation, animals with R113Q-KRKR express many of the genes affected in AR113Q animals (9). These two strains of mice provide a useful tool to study the effects of gain and/or loss of function of AR transcriptional regulation in SBMA.…”

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confidence: 99%

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Fighting polyglutamine disease by wrestling with SUMO

Craig¹,

Henley²

2015

J. Clin. Invest.

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C o m m e n t a r y4 Polyglutamine disorders and SUMOylationPatients with spinobulbar muscular atrophy (SBMA) exhibit a progressive loss of muscle function due to motor neuron degeneration. SBMA is the result of a polyglutamine (polyQ) expansion in the androgen receptor (AR) transcription factor. PolyQ AR has reduced transcriptional activity, leading to a toxic gain-of-function effect via disruption of downstream pathways, and is prone to unfolding and oligomerization, resulting in the formation of intracellular aggregates (1). It is currently unclear whether these AR aggregates are directly cytotoxic, and it is also unknown what role the loss of intrinsic AR transcriptional activity plays in SBMA pathogenesis. SUMOylation is a posttranslational modification of lysine residues in target proteins by the small ubiquitin-like modifier (SUMO), which is a key regulator of multiple cell pathways (2). It is becoming increasingly apparent that SUMOylation plays important roles in a diverse range of neuronal processes in both health and disease (3). In particular, SUMOylation has been implicated in the pathology of polyQ disorders (4), most notably Huntington's disease, where SUMOylation of huntingtin (HTT) is responsible for the degeneration of striatal neurons (5).The AR is SUMOylated at two lysine residues, resulting in attenuation of transcriptional activity (6), reduced aggregation of polyQ AR (7), and inhibition of ubiquitination at these lysine residues (8). SUMOylation is unchanged between WT and polyQ forms of AR; therefore, it is not clear whether SUMOylation of polyQ AR contributes to the pathology of SBMA.In this issue, Chua et al. report on their development of knockin mice in which the native Ar locus was replaced with one encoding either a polyQ AR (AR113Q) or a nonSUMOylatable polyQ AR in which lysine residues 385 and 518 were mutated to arginine (AR113Q-KRKR) (9). Because SUMOylation inhibits AR transcriptional activity, it was predicted that the AR113Q-KRKR mutant would rescue some of the transcription deficiencies caused by AR113Q. This experimental design allowed Chua and colleagues to test whether deficient transcription contributes to SBMA pathology and to determine whether SUMOylation is a potential therapeutic target in SBMA. Additionally, the results provide some insights into the involvement of SUMOylation and polyQ AR aggregation in the disease.Is deficient transcriptional regulation responsible for SBMA pathology?The relative contributions of toxic gain of AR function and loss of intrinsic AR transcriptional activity to the etiology of SBMA have been a matter of some debate. Chua et al. demonstrated that, compared with mice harboring the AR113Q mutation, animals with R113Q-KRKR express many of the genes affected in AR113Q animals (9). These two strains of mice provide a useful tool to study the effects of gain and/or loss of function of AR transcriptional regulation in SBMA. Intriguingly, some, but not all, of the defects in the R113Q mouse model of SBMA could be attributed to the loss of AR-d...

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confidence: 86%

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confidence: 89%

Section: Perspectives: Interesting Basic Science And/or a Viable Treamentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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