Spinal and bulbar muscular atrophy (SBMA) is an inherited disease that eventually leads to degeneration in motor neurons and weakness in muscles. It is caused by a specific genetic mutation in the gene that encodes the androgen receptor protein, which leads to the production of a mutant protein that is larger than normal. Similar mutations in other genes can lead to the development of other so-called ‘polyglutamine’ diseases such as Huntington's disease and spinocerebellar ataxia. However, the precise details of how these mutations lead to disease symptoms are not known, and there are currently no effective ways of treating these conditions.

Previous research has shown that an enzyme called Nemo-like kinase (or NLK for short) regulates the normal androgen receptor in cancer cells. NLK has kinase activity, that is, it adds phosphate molecules to other proteins to regulate their activity. Todd et al. used human cells, fruit flies, and mice as model systems to investigate whether NLK is involved in the development of SBMA.

The experiments show that NLK promotes the development of features associated with SBMA in all three models. The kinase activity of NLK is required for these features to develop. Todd et al. also found that NLK can bind to and add phosphate molecules to the mutant version of the androgen receptor protein. This causes the mutant androgen receptor proteins to accumulate and increases the ability of the mutant proteins to activate particular genes.

Todd et al.'s findings suggest that NLK promotes the development of SBMA by interacting with the mutant androgen receptor. Previous studies have shown that NLK is able to modulate the development of spinocerebellar ataxia type 1, which suggests that NLK may also play an important role in other polyglutamine diseases. The next challenge will be to fully understand the role of NLK in these diseases, which may aid future efforts to develop new treatments.

Spinal and bulbar muscular atrophy (SBMA; MIM #313200) is an X-linked progressive neuromuscular disease (Kennedy et al., 1968). Patients present in midlife with weakness of the limb and facial muscles, the latter of which often progress to dysarthria and dysphagia, occasionally leading to fatality. SBMA patients also commonly suffer from mild androgen insensitivity, presenting with gynecomastia, testicular atrophy, and decreased fertility (Katsuno et al., 2012). SBMA was originally defined as a neurodegenerative disease affecting the proximal spinal and bulbar motoneurons, and muscle atrophy was considered secondary to motoneuron degeneration. Current opinion in the field of SBMA research, however, now favors a model in which SBMA also directly affects the skeletal muscles (Yu et al., 2006; Jordan and Lieberman, 2008; Monks et al., 2008; Boyer et al., 2013; Malena et al., 2013; Oki et al., 2015), and, in fact, recent studies have shown that removing or decreasing the expression of the mutant protein within skeletal muscle is sufficient to rescue SBMA phenotypes in vivo (Cortes et al., 2014; Lieberman et al., 2014). This model of disease is supported by the finding that, in conjunction with neuronal loss, patients also show elevated creatine kinase levels and evidence of myopathic changes on biopsy (Sorarù et al., 2008; Chahin and Sorenson, 2009).

SBMA is caused by the expansion of a polymorphic CAG trinucleotide repeat located in the first exon of the Androgen Receptor (AR) gene (La Spada et al., 1991). In wild-type AR, this repeat region encodes a stretch of 6–36 glutamines (Q). In SBMA patients, in contrast, the region is expanded to 37 to 70Q, resulting in pathogenesis via a gain-of-function and partial loss-of-function mechanism (Katsuno et al., 2012). SBMA is therefore one of nine identified polyglutamine (polyQ) repeat diseases, along with Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17. PolyQ expansion renders the host protein toxic, resulting in the formation of mutant protein aggregates and cell death; and the commonalities in the nature of the mutation and the presentation of the different polyQ disorders suggest the presence of a common pathogenic mechanism (Orr, 2001). Nonetheless, this mechanism has remained elusive and to date there are no cures or even effective therapies for most of these diseases.

AR is a well-studied steroid hormone receptor that also plays a crucial role in additional diseases including androgen insensitivity syndrome and prostate cancer (Bennett et al., 2010). Studies focusing on wild-type AR function and its role in other disease contexts can therefore shed light on SBMA pathogenesis. For instance, the main function of AR is to bind androgenic hormones, either testosterone or 5α-dihydrotestosterone (DHT), in the cytoplasm, and then translocate into the nucleus to act as a DNA-binding transcription factor that regulates androgen-dependent target gene expression (Bennett et al., 2010). SBMA pathogenesis is dependent upon the presence of circulating androgens and is therefore only observed in males, with homozygous female carriers showing only mild symptoms (Katsuno et al., 2012). The importance of androgens to the disease has also been clearly shown in mouse models of SBMA (Katsuno et al., 2002; Chevalier-Larsen et al., 2004). Furthermore, the nuclear translocation of AR is also crucial for pathogenesis (Takeyama et al., 2002; Montie et al., 2009; Nedelsky et al., 2010). It has also been suggested that an AR interdomain interaction known as the amino (N)-terminal–carboxy (C)-terminal (N/C) interaction is important for SBMA (Orr et al., 2010), as are the DNA-binding ability of AR (Nedelsky et al., 2010) and its post-translational modification including acetylation (Montie et al., 2011), methylation (Scaramuzzino et al., 2015), and other modifications (Katsuno et al., 2012). In addition, several cofactors and regulators of AR can influence SBMA disease pathogenesis (McCampbell et al., 2000; Taylor et al., 2003; Palazzolo et al., 2007; Suzuki et al., 2009; Nedelsky et al., 2010; Montie et al., 2011). Despite extensive studies, however, a precise molecular explanation for SBMA pathology has remained elusive.

Given the importance of androgens to SBMA pathogenesis, many approaches to SBMA therapeutics have focused upon depleting androgen levels in patients (Banno et al., 2009; Katsuno et al., 2010b; Fernández-Rhodes et al., 2011; Yamamoto et al., 2013). Unfortunately, these strategies have not yielded significant results in clinical trials; hence, new approaches are necessary. It has been shown that within prostate cancer cells, wild-type AR physically interacts with Nemo-like kinase (NLK) and that NLK is able to regulate the activity and transcription of AR in this context (Emami et al., 2009). Interestingly, studies show that NLK interacts either directly or indirectly with a number of neurodegenerative disease-related proteins (Lim et al., 2006; Ju et al., 2013), suggesting that it may play an important role in the pathogenesis of neurodegenerative proteinopathies. Indeed, we have found that loss of one copy of Nlk (resulting in a 50% reduction in protein expression) is beneficial in mouse models of the polyQ disease SCA1 (Ju et al., 2013). NLK is an evolutionarily conserved mitogen-activated protein kinase -like serine/threonine kinase primarily studied in lower model organisms, where it has been linked to a number of signaling pathways (Ishitani et al., 1999; Ohkawara et al., 2004; Ishitani et al., 2010; Ishitani and Ishitani, 2013). In this study, we tested the hypothesis that NLK may play a role in SBMA pathogenesis. We present evidence that NLK influences the aggregation and toxicity of polyQ-expanded AR across multiple model systems, using cell culture, Drosophila, and mouse. Loss of one copy of Nlk was able to partially rescue disease phenotypes in both Drosophila and mouse models of SBMA. Furthermore, this 50% reduction in NLK protein expression dramatically extended the lifespan of SBMA mice. Finally, we investigated the molecular mechanisms by which NLK mediates these effects on SBMA and suggest a model in which NLK interacts with and phosphorylates AR, inhibiting its intramolecular N/C interaction and thereby promoting gene transcription via the AR activation function 2 (AF-2) domain. This effect on AR activity could then modulate SBMA-related aberrant AR-dependent gene transcription. In addition, reduced NLK expression can rescue the toxic effects of an N-terminal fragment of AR, suggesting that NLK can regulate the mutant AR protein—even in the absence of DNA binding and AR-responsive gene transcription.

SBMA is a devastating neuromuscular disease without any cure or effective therapy to date. In this study, we explored whether and how NLK could modulate the pathogenesis of SBMA. By utilizing a variety of model systems, we clearly show that NLK is a key regulatory factor capable of modulating AR activity and SBMA pathology. Using a combination of cell culture, Drosophila, and mouse models, we show that reduced expression of NLK suppresses, while increased expression exacerbates, mutant AR-associated SBMA pathology, including protein aggregation, cellular toxicity and degeneration, and animal lethality phenotypes. It is particularly intriguing that the effects of NLK on the mutant polyQ-expanded AR and SBMA are consistent across different model systems, as this suggests that the role of NLK in SBMA pathogenesis is fundamental. Furthermore, all of these effects are clearly dependent on the kinase activity of NLK. Our work therefore strongly suggests that a reduction in NLK expression or enzymatic activity could be beneficial for SBMA patients.

Of particular importance is our finding that a 50% reduction in NLK expression partially rescues the phenotypes of an SBMA mouse model (Figures 6–8). This improvement in pathology was seen at 20 weeks of age in these mice and was more robust at the later time point of 30 weeks. By very late time points (i.e., 40 weeks), however, a reduction in NLK expression resulted in an improvement of only some of SBMA phenotypes assayed (Figures 6, 8E), and did not show a robust effect in other assays (Figures 7, 8G). This suggests that a reduction in NLK expression may act to delay disease progression in this model, but is not sufficient to completely prevent the onset of the full SBMA phenotype. It should be noted that the majority of BAC fxAR121 mice die before reaching this final time point, however, and so we cannot rule out the possibility that the small cohort of mice analyzed at 40 weeks represent an ‘escaper’ subset of SBMA mice that are slightly healthier than the average BAC fxAR121 mouse. The reasons for the variation in the SBMA phenotype in these mice are not known, but may be interesting to investigate in the future. It is also worth mentioning that we analyzed the mice on a C57/129 F1 hybrid genetic background. Although they can be considered to be on a pure background for the purpose of this study, we cannot rule out the possibility of mouse background effects. Future studies on a different pure genetic background and/or using NLK inhibitors would be useful in corroborating our findings.

In this study, we uncovered some molecular mechanisms that we predict underlie the role of NLK in SBMA at the cellular level. First, NLK interacts with mutant AR at the N-terminal region of the protein, and, interestingly, polyQ expansion results in a more robust interaction between NLK and mutant AR in comparison to wild-type AR (Figure 1A–C). Second, consistent with our data that NLK modulates SBMA features in a kinase activity-dependent manner, NLK promotes the phosphorylation of AR, either directly or indirectly, at multiple sites, including S81 and S308 (Figure 9). NLK-induced changes in AR-S81 phosphorylation can be detected in vivo in mice, and AR-S81 phosphorylation likely contributes to the effect of NLK on SBMA pathology in cell culture and Drosophila models (Figure 10). Interestingly, however, the S81A mutation decreased, but did not completely abolish, the NLK-mediated effects on mutant AR aggregation (Figure 10A). This indicates that, while AR-S81 is likely an important NLK phosphorylation site in the N-terminal region of AR, there may be other NLK target sites outside of this region that also contribute to NLK-dependent AR toxicity in SBMA. Finally, NLK can affect the transcriptional activity of the mutant AR protein, and, once again, this is dependent on its kinase activity (Figure 11). Unlike aggregation, which is dependent on the presence of a polyQ expansion, this effect is seen with both wild-type and mutant AR. This suggests that NLK normally acts as an AR cofactor or regulator. PolyQ expansion, while resulting in the aggregation of the protein, also affects the activity of the AR monomer, whose altered function in target gene transcription may exert pathology in SBMA (Nedelsky et al., 2010). The ability of NLK to promote the activity of the mutant AR could therefore exacerbate this polyQ-induced protein dysfunction. We suspect that both the modulation of mutant AR aggregation and the misregulation of its native functions ultimately contribute to SBMA pathology, and our data suggest that NLK influences both of these pathomechanisms (Figure 12).

Figure 12

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The binding of NLK to AR, and likely its subsequent phosphorylation, strongly inhibit the AR N/C interaction, and yet paradoxically increase AR-mediated gene transcription (Figure 11A–C). This led us to investigate whether NLK could regulate AR activity via the AF-2 domain, and indeed, we found that complete inhibition of cofactor binding at the AR AF-2 domain strongly compromised the ability of NLK to increase AR transcriptional activity (Figure 11E). The NLK effect on AR activity was not completely abolished by this mutation, however, suggesting that NLK may promote AF-1-dependent transcription, as well. Furthermore, the E897K mutation compromised the effect of NLK on AR activity more so than the K720A mutation (Figure 11E). As these mutations both completely abolish LxxLL motif binding, this suggests that NLK may preferentially allow for FxxLF motif-containing cofactor binding at the AR AF-2 domain, and this possibility warrants further investigation. Once again, as the effect of NLK on AR transactivation and on the AR N/C interaction are seen with both wild-type and mutant AR, this role for NLK in the regulation of AR AF-2 cofactor interactions is likely a normal function of NLK in AR signaling. Given that NLK promotes SBMA pathology, this may suggest that the AR AF-2 domain is important for SBMA pathogenesis. Interestingly, a separate study found that the retinal degeneration phenotypes in a full-length mutant AR Drosophila model were also dependent upon the AF-2 domain of AR. This study also found that the E897K mutation at the AF-2 domain led to a more robust rescue of mutant AR phenotypes than K720A, again demonstrating that the ability of the AR AF-2 domain to bind FxxLF-containing cofactors may be important for SBMA pathogenesis (Nedelsky et al., 2010).

We also find it intriguing that the effect of NLK on AR molecular functions is very similar to that of the primate-specific Melanoma Antigen Gene Protein 11 (MAGE-11). MAGE-11 has been reported to bind AR specifically at the ²³FQNLF²⁷ motif in the N-terminal region of the AR protein to prevent the N/C interaction and allow for cofactor binding at the AF-2 domain (Bai et al., 2005). MAGE-11 is also known to directly bridge interactions between AR and various cofactors, including TIF2 and p300, resulting in a synergistic activation of AR-dependent gene transcription (Askew et al., 2009, 2010). Together with our data, this suggests that inhibition of the N/C interaction by specific AR cofactors represents a unique and intriguing approach to regulating AF-domain dominance in AR target gene transcription. It will be interesting to investigate whether there is any cross-talk between NLK and MAGE-11 in AR-mediated gene activation and, perhaps, even in SBMA disease pathogenesis.

We suspect that the NLK-mediated increase in AR transactivation results from an increase in cofactor binding at the AR AF-2 domain, thereby supporting a model in which AF-2-mediated interactions are important for SBMA pathogenesis. And yet, it is also clear that inhibiting the N/C interaction via point mutations in the AR ²³FQNLF²⁷ motif reduces mutant AR aggregation and toxicity (Figure 11—figure supplement 3A–C and Orr et al., 2010), features that NLK clearly promotes. One explanation for this seemingly conflicting data is that the binding of NLK to AR and the subsequent phosphorylation of the AR protein, perhaps at S81, elicit an effect on the AR protein that is similar to the effect of the N/C interaction. In this model, NLK binding and the N/C interaction are parallel means of triggering a similar downstream pathogenic response. It should be stressed, however, that binding and phosphorylation by NLK does not preclude the need for AR ligand binding, as aggregation (Figure 1G and Figure 1—figure supplement 1), gene transcription (Figure 11—figure supplement 1A), and the formation of the AR AF-2 domain (Wärnmark et al., 2003) all depend upon the presence of androgens, and NLK has no effect on these features without ligand. Furthermore, the exact details of this downstream pathway are still not completely clear. For instance, toxicity could arise from aberrant AR-mediated gene transcription (via a combination of AF-1 and AF-2 dependent mechanisms), the sequestration of various cofactors into aggregates, the inability of certain cells to handle the accumulation of toxic AR conformers, or via some other as-yet-unknown pathogenic factors. Or, perhaps more likely, SBMA may arise from a combination of the above (Figure 12).

Given that NLK interacts with and phosphorylates the mutant AR (Figures 1, 9), we suspect that it is acting cell autonomously to regulate AR activity based on the mechanism we propose. As our mouse studies were carried out using a constitutive knockdown of NLK, however, we cannot at this time determine where NLK exerts its effects on SBMA pathology. In other words, it could be regulating mutant AR activity in the spinal motor neurons, the skeletal muscle, or both. Future investigations using targeted NLK inhibitors or tissue-specific knockdown using both this and other SBMA mouse models could address these questions. It is also interesting to note that, although our data show that NLK can influence the aggregation of the mutant AR across multiple models, and that NLK has a robust effect on AR transactivation activity in cells, we saw only a partial rescue of SBMA muscle and motor neuron pathology with a reduction in NLK expression in mice. Why we did not see a more robust improvement of these phenotypes is an intriguing question. A simple explanation may be that the remaining 50% of NLK expression, AR phosphorylation, and mutant protein aggregation is enough to allow for the toxic effects of the mutant AR that directly result in decreased muscle fiber and motor neuron size. A more complete knockout of NLK would thus be needed to prevent degeneration. Mice heterozygous for the Nlk gene trap allele are largely normal, suggesting either that this lower expression of NLK is enough to adequately carry out wild-type functions of NLK in the adult mouse, or that some other factor or pathway compensates for the decrease in active NLK. It is possible that such a compensatory factor or pathway may also contribute to mutant AR-induced pathology when NLK expression is reduced.

Data presented here and in a previous publication (Ju et al., 2013) suggest that NLK is able to regulate the pathogenesis of two separate polyQ diseases: SBMA and SCA1. In both cases, evidence suggests that NLK binds to and phosphorylates the mutant protein and thereby regulates its aggregation and activity. Yet, why NLK interacts with multiple polyQ proteins is an open question that warrants future investigation. We also noted that co-expression of NLK seemed to increase AR protein levels in NSC-34 cells and in the AR61Q Drosophila model, as well as separately influence its propensity to aggregate. This suggests that NLK may play a role in the stabilization of AR, specifically at the protein level, as both of these systems express AR under the control of exogenous promoters. In the BAC fxAR121 mice, however, the AR121Q protein levels between mice with full NLK expression and those with a 50% reduction in NLK are not significantly different across the population assayed (data not shown). As all the mice assayed did show a rescue in the degenerative phenotype, however, we concluded that another mechanism must be playing a role in these mice and therefore investigated the possibility of a direct interaction between NLK and AR. That direct mechanism is the focus of the current study. Nonetheless, we noted that a subset of about 30–40% of the mice did show a reduction in mutant AR protein levels with a reduction in NLK expression. We therefore speculate that NLK may also play a role in protein clearance pathways, and that this, in turn, may contribute to the ability of NLK to regulate mutant protein aggregation and toxicity in varying disease cases. We ultimately suspect that both direct and indirect regulation of mutant protein expression/aggregation and activity underlies the role of NLK in disease.

Lastly, although there is still much to be understood about the precise molecular mechanisms underlying SBMA and the role of NLK therein, our data clearly show that NLK normally promotes the disease condition and that reduction of NLK expression or activity is sufficient to partially rescue SBMA pathogenicity. We are confident in this conclusion because we utilized a multi-system approach to address the question. NLK is therefore a novel and interesting putative therapeutic target. We should note that complete loss of NLK function may cause severe problems, however, since NLK plays a role in multiple signaling pathways (Ishitani et al., 1999; Ohkawara et al., 2004; Ishitani et al., 2010; Ishitani and Ishitani, 2013). Nonetheless, Nlk^gt/+ heterozygous mice are generally healthy and our study provides convincing evidence that a 50% reduction in NLK protects against SBMA pathogenesis in vivo (Figures 6–8). Thus, this study suggests that putative treatments that target NLK may not need to completely inactivate the protein to generate a therapeutic effect. It will be very interesting to determine if pharmacologically inhibiting NLK can also rescue SBMA features at the mammalian level.

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Author details

1. Tiffany W Todd

   Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States

   Contribution

   TWT, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Hiroshi Kokubu

   Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States

   Contribution

   HK, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Helen C Miranda

   Departments of Cellular and Molecular Medicine, Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States

   Contribution

   HCM, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

4. Constanza J Cortes

   Departments of Cellular and Molecular Medicine, Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States

   Contribution

   CJC, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

5. Albert R La Spada

   Departments of Cellular and Molecular Medicine, Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States

   Contribution

   ARLS, Conception and design, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Janghoo Lim

   Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States

   Contribution

   JL, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   janghoo.lim@yale.edu

   Competing interests

   The authors declare that no competing interests exist.

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