Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity

Palazzolo, Isabella; Burnett, Barrington G.; Young, Jessica E.; Brenne, Phebe L.; Spada, Albert R. La; Fischbeck, Kenneth H.; Howell, Brian W.; Pennuto, Maria

doi:10.1093/hmg/ddm109

Cited by 129 publications

(166 citation statements)

References 37 publications

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“…A reduction in AR concentration is the likely basis for the ameliorating effects of androgen blockade in mouse models of SBMA (70 -72). A reduction in ligand binding and stabilization is also the likely mechanism for the recently described protective effects of IGF1-mediated AR phosphorylation by AKT (73). Other approaches, such as inhibition of HSP90-dependent transport, also appear to protect against AR aggregation by facilitating the degradation and turnover of the receptor (4).…”

Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Mukherjee¹,

Thomas

Dadgar

et al. 2009

Journal of Biological Chemistry

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The neurodegenerative disorder spinal and bulbar muscular atrophy or Kennedy disease is caused by a CAG trinucleotide repeat expansion within the androgen receptor (AR) gene. The resulting expanded polyglutamine tract in the N-terminal region of the receptor renders AR prone to ligand-dependent misfolding and formation of oligomers and aggregates that are linked to neuronal toxicity. How AR misfolding is influenced by post-translational modifications, however, is poorly understood. AR is a target of SUMOylation, and this modification inhibits AR activity in a promoter context-dependent manner. SUMOylation is up-regulated in response to multiple forms of cellular stress and may therefore play an important cytoprotective role. Consistent with this view, we find that gratuitous enhancement of overall SUMOylation significantly reduced the formation of polyglutamine-expanded AR aggregates without affecting the levels of the receptor. Remarkably, this effect requires SUMOylation of AR itself because it depends on intact AR SUMOylation sites. Functional analyses, however, indicate that the protective effects of enhanced AR SUMOylation are not due to alterations in AR transcriptional activity because a branched protein structure in the appropriate context of the N-terminal region of AR is necessary to antagonize aggregation but not for inhibiting AR transactivation. Remarkably, small ubiquitin-like modifier (SUMO) attenuates AR aggregation through a unique mechanism that does not depend on critical features essential for its interaction with canonical SUMO binding motifs. Our findings therefore reveal a novel function of SUMOylation and suggest that approaches that enhance AR SUMOylation may be of clinical use in polyglutamine expansion diseases.Spinal and bulbar muscular atrophy (SBMA), 2 or Kennedy disease, is an inherited degenerative disorder of lower motor neurons (1, 2). SBMA is characterized by muscle cramps and fasciculations followed by progressive weakness and atrophy of the proximal limb and bulbar muscles (3-5). The causative genetic alteration is an expansion in the length of a CAG trinucleotide repeat within the coding sequence of the androgen receptor (AR) gene, leading to an expanded polyglutamine tract in the N-terminal transcriptional regulatory domain of the receptor. A similar expansion within the coding sequence of a set of additional genes is responsible for other members of the polyglutamine class of protein folding diseases (6, 7), which include Huntington disease, several autosomal dominant spinocerebellar ataxias (SCAs) (8), and dentatorubral-pallidoluysian atrophy (9, 10).The length of the CAG repeat within AR is correlated to the severity of SBMA. Although the normal repeat length is highly polymorphic and ranges between 9 and 36 copies, overt disease is associated with lengths in the range of 38 -62 repeats. The presence of an expanded polyglutamine tract within AR renders the protein prone to hormone-dependent misfolding, oligomerization, and aggregation and to the formation of microscopica...

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Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Mukherjee¹,

Thomas

Dadgar

et al. 2009

Journal of Biological Chemistry

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“…IGF1 signaling can have neuroprotective effects in the context of specific mutant polyglutamine proteins (32,33). Indeed, IGF1 is a pleiotropic neuroprotective factor that may prevent the tissue atrophy, vascular dysfunction, and accumulation of deleterious products often associated with the aging brain (34).…”

Section: Discussion Common Transcriptional Changes Occur In Early-symmentioning

confidence: 99%

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Gatchel¹,

Watase

Thaller³

et al. 2008

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

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Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders, each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cellautonomous mechanism and was concomitant with activation of the insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis.cerebellum ͉ neurodegeneration ͉ polyglutamine ͉ Purkinje cell ͉ granule neuron P olyglutamine diseases are a group of inherited neurodegenerative disorders that include spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). They are caused by expansion of CAG repeats encoding a polyglutamine tract in different proteins (1). Evidence suggests that the polyglutamine expansion confers toxicity predominantly through a gain-of-function mechanism, although loss of function may also play a role (1, 2). Despite widespread expression of the disease proteins in the central nervous system (CNS), there is selective vulnerability of specific neurons in each disease (1). Such selective neuronal vulnerability gives rise to the specific features of each disease.SCA1 and SCA7 have distinct features while also sharing some key similarities. In SCA1, primary symptoms include ataxia, dysarthria, and bulbar dysfunction, whereas cognitive impairment is more varied (1). This presentation is associated with cerebellar atrophy and loss of Purkinje cells (PCs) and secondary loss of granule neurons (1). In SCA7, progressive visual loss, cerebellar ataxia, and dysarthria are the most common clinical features (3). In addition to retinal degeneration, cerebellar PCs and neurons of the dentate nucleus and inferior olive are among the earliest to degenerate (3).Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation (4-8), and transcriptional defects can be detected in e...

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“…Pulse-chase analysis was performed as previously described (34). In brief, HEK293T cells were incubated in cysteine-methioninefree medium (Sigma-Aldrich) for 2 h or 12 h followed by incubation in cysteinemethionine-free medium containing 100 Ci of 35 S-labeled cysteine-methionine (GE Healthcare, Piscataway, NJ) for 1 h. After labeling, the cells were washed once with culture medium containing 10-fold excess of unlabeled methionine and cysteine (5 mM each) and then incubated further in the same medium.…”

Section: Methodsmentioning

confidence: 99%

Regulation of SMN Protein Stability

Burnett

Muñoz

Tandon

et al. 2009

Molecular and Cellular Biology

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Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMN⌬7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMN⌬7 proteins have been largely unexplored. Using pulsechase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMN⌬7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.

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Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity

Cited by 129 publications

References 37 publications

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7

Regulation of SMN Protein Stability

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