AR CAG Repeats and Spinal and Bulbar Muscular Atrophy

The AR CAG repeat polymorphism influences tissue response to androgens

An increase in repeats of the cytosine-adenine-guanine (CAG) trinucleotide sequence in the N-terminal domain of the androgen receptor is inhibitory of appropriate transactivation function ​(Chamberlain et al., 1994)​, entailing weaker transcriptional activity ​(Singh et al., 2007)​. Patrizio et al reported a statistically significant association between longer CAG repeats and infertility (mean length 25) when compared with healthy controls (mean length 22), particularly apparent in those with extremely severe oligozoospermia ​(Patrizio et al., 2001)​. AR CAG repeat sequence length is associated with a higher risk of symptomatic late-onset hypogonadism in men ​(Hong et al., 2018; Kim et al., 2018)​. As well as physiological outcomes, the CAGn has been associated with evolutionary-relevant male life history strategies ​(Gettler et al., 2017)​.

Huhtaniemi et al. analysed valuable and unique data from the European Male Ageing Study, comprising AR CAG repeat lengths and endocrine and clinical characteristics of nearly 3000 men aged 40 –79. Coordinated by centres across Europe ​(Lee et al., 2009)​, this dataset benefits distinctly from standardisation and large sample size. Analysis revealed that, while below the 40 CAGn threshold considered denotive of SBMA ​(Spada et al., 1991)​, as the Exon 1 CAG repeat length extended, the length of the AR polyglutamine tract repeat correlated directly to all measures of serum testosterone (total, bioavailable, free) and strongly positively correlated to T and E2 in circulation. No symptoms or signs of androgen deficiency correlated to the CAG repeat length, suggesting that in the presence of greater polyQ expansion, deficiency of androgen action may be compensated for by a concomitant increase in the production of androgens under normal hypothalamic-pituitary-testicular axis conditions ​(Huhtaniemi et al., 2009)​. This compensation had similarly been hypothesised by Skjærpe et al. who also reported a positive association between CAG repeat length and free and total testosterone ​(Skjaerpe et al., 2008)​.

Although not universal, assumedly due to reasons including fluctuations in testosterone levels and the cross-sectional nature of some studies ​(Harkonen et al., 2003)​, this positive correlation of longer CAG stretches with free and total testosterone is well established ​(Crabbe et al., 2007; Gong et al., 2014; Harkonen et al., 2003; Krithivas et al., 1999; Owens et al., 2018; Stanworth et al., 2008)​. Khan et al. additionally observed this in a large cohort of 400 men ​(Khan et al., 2018)​. Their study noted that the IIEF-15 scores negatively correlated to long CAGn repeats despite higher testosterone levels, concluding that long CAGn repeats impair the effects of testosterone, particularly on erectile function. Liu et al had previously reported, in a cohort of 478 Taiwanese males aged 41 to 83, that long CAGn repeats were an independent risk factor for erectile dysfunction in men with testosterone above 3.3ng/mL but, interestingly, not 3.3ng/mL or below ​(Liu et al., 2015)​. This finding was additionally corroborated by Tirabassi et al ​(Tirabassi et al., 2016)​. Speculatively, this evidence suggests higher testosterone may exert a negative physiological effect on tissues expressing expanded CAGn AR before reaching the repeat threshold of SBMA, in which toxicity is ligand dependent. The relationship between AR CAGn and optimal function is not strictly linear: Low repeat lengths are also associated with suboptimal function. In vitro investigations by Nenonen et al. revealed a 22 CAG genotype had the highest AR-mediated transcription with the least protein compared with 16 CAG and 28 CAG. ​(H. Nenonen et al., 2009)​ In agreement, analysis of 4000 men revealed lengths close to this median confine a lower risk of infertility ​(H. A. Nenonen et al., 2010)​.

Despite the vital role of testosterone centrally ​(Santi et al., 2018)​ and peripherally for male sexual function and maintenance ​(Corona et al., 2016; Traish, 2008)​, studies of healthy men have failed to denote a relevant testosterone threshold for erectile dysfunction ​(Lackner et al., 2011)​. Androgen-induced target activities are attenuated corresponding to the length of triplet residues ​(Zitzmann, 2008)​ and the result of exogenous testosterone treatment is markedly modulated by CAG repeat polymorphism ​(Francomano et al., 2013)​. Owing to this relationship, it has been suggested that existing thresholds of hypogonadism and consequential indications are likely to be replaced with a continuum spanned by genetics and symptom specificity ​(Zitzmann, 2009)​. Recently, Escobedo et al. demonstrated the tandem CAG repeat sequence folds into a helical structure, with propensity of helicity correlating positively to sequence length. An accumulation of unconventional hydrogen bond donations from glutamine side chains to the main chain carbonyl of the residue at relative position i−4 confers a gain of stability to the polyQ helix and could provide a rationale for length-dependent impairment of transactivation function ​(Escobedo et al., 2019)​. Collectively, research illustrates that the available level of ligand is not an absolute determinant of optimum androgenic function, and much is dependent on its transcription factor in target tissues. The effect of agonists as beneficial or detrimental is determined specifically by the tissue of action ​(Narayanan et al., 2018)​.

SBMA

X-linked Spinal and Bulbar Muscular Atrophy, also known as Kennedy’s disease, is a condition which effects multiple bodily systems and organs ​(Manzano et al., 2018; Sperfeld et al., 2002)​. SBMA is caused by an expansion of the CAG trinucleotide repeat polyglutamine tract in the first exon of the androgen receptor ​(Spada et al., 1991)​, with an excess of 38 repeats denotive of the pathogenesis ​(G. Querin et al., 2017)​.

SBMA is rare, occurring in 1 per 400,000 men per year ​(Fischbeck, 1997)​. This rarity has led to calls for the establishment of international multi-center networks to speed understanding and progress ​(Fratta et al., 2014; G. Querin et al., 2017)​. Poor clinical awareness, frequent improper diagnosis and confusion with other diseases likely result in an underestimated prevalence ​(G. Querin et al., 2017)​. In cohorts of 47 and 46 patients considered, 32% and 30% respectively had received an alternative diagnosis at first ​(Fratta et al., 2014; Rhodes et al., 2009)​. SBMA usually becomes notably symptomatic in middle age or later ​(Katsuno et al., 2012)​, however initial symptoms often begin in adolescence, long before clinical assessment ​(Sperfeld et al., 2002)​. In line with the inhibitory action of the polyglutamine tract on AR transactivation, tandem CAG repeat length has been correlated to androgen insensitivity in SBMA ​(Dejager et al., 2002)​. CAG repeat length correlates inversely with age at onset but does not always correlate to disease severity or progression ​(Doyu et al., 1992; Fratta et al., 2014; Andrew P. Lieberman et al., 2014; Rhodes et al., 2009)​. Epigenetic contributions to the late onset nature of SBMA are likely ​(Kondo et al., 2019)​. Progression is gradual and life expectancy is averagely insignificantly decreased ​(Chahin et al., 2008)​. The breadth of the clinical spectrum and involvement of testosterone target tissue likely reflects the ubiquitous expression of the androgen receptor throughout the central nervous system and peripheral tissues ​(H. Adachi, 2005)​. The complex clinical picture that results has been described by Manzano et al. as an “interplay between differentially affected tissues, which struggle to cooperate to maintain homeostasis” ​(Manzano et al., 2018)​.

Characteristic symptoms are proximal and distal weakness and proximal muscle atrophy. Bulbar muscle involvement accounts for dysarthria, dysphagia, hypernasality and decreased range of pitch and loudness ​(Pennuto & Rinaldi, 2018; G. Querin et al., 2017)​. Other common symptoms include fasciculations, cramps, tremor, reduced or absent deep tendon reflexes, loss of sensory functions in extremities, loss of vibratory sensation, tongue wasting, gynecomastia, sexual dysfunction, testicular atrophy and fertility problems including oligospermia/azoospermia. ​(Dahlqvist et al., 2019; Dejager et al., 2002; Fratta et al., 2014; Kennedy et al., 1968; Polo et al., 1996; G. Querin et al., 2017; Udd et al., 2009)​. Symptoms including gynecomastia, hand tremors, muscular cramps, myalgias, premature exhaustion during physical exercise and feet numbness can present before the onset of weakness ​(Finsterer & Scorza, 2019; Finsterer & Soraru, 2015)​. Libido loss presents and can be unappreciated due to the late onset ​(G. Querin et al., 2017)​. Abdominal obesity, dyslipidemia, glucose intolerance and liver problems represent a commonly seen metabolic involvement and these patients can frequently develop metabolic syndrome ​(Dejager et al., 2002; Pennuto & Rinaldi, 2018; G. Querin et al., 2017; Rosenbohm et al., 2018)​. Heart rhythm abnormalities including Brugada syndrome can occur ​(Araki et al., 2014; Giorgia Querin et al., 2015)​. Alterations in bone mineral density including lumbar density scores above controls, lumbar and/or femoral osteopenia, and osteoporosis are reported without correlation to LH, testosterone or vitamin D determinations. The frequency of lower urinary tract symptoms exceeds that of the general population significantly ​(Giorgia Querin et al., 2015)​. Interestingly, AR133Q knock-in mouse models exhibit significant atrophy and abnormal spontaneous myotonic discharges in the levator ani/bulbocavernosus (LABC) muscles, suggesting alteration to lower urinary tract muscle membrane excitability that could be responsible for the obstructive LUTS and associated death in these models ​(Yu, 2006)​. Hypospadias has been suggested as potentially underreported feature of the SBMA phenotype ​(Nordenvall et al., 2016)​.

While traditional focus has been on the muscular symptoms and long-associated motor neuron degeneration ​(Lombardi, Querin, et al., 2019)​, this can be misleading ​(Finsterer & Scorza, 2019; Sperfeld et al., 2002)​. The systemic, endocrinological and neuropsychological effects are now known to be of equal importance to both the clinical picture and the quality of life of patients ​(G. Querin et al., 2017; Giorgia Querin et al., 2018)​. SBMA can manifest in absence of neuromuscular complaints or symptoms, presenting with an endocrine phenotype comprising of symptoms including gynecomastia, testicular atrophy, hypercholesterolemia and diabetes mellitus ​(Battaglia et al., 2003)​. Nonclassical symptoms including erectile dysfunction can be cited by patients as amongst their most disabling symptoms ​(Fratta et al., 2014)​. Sexual dysfunction across domains including orgasm function, erectile function and satisfaction is commonly reported ​(Dahlqvist et al., 2019)​. In a large cohort of 73 patients, excluding ten patients who refused to answer, all patients were found to have mild-to-severe erectile dysfunction per IIEF (mean 15.9±7.6; range 0–25) ​(Giorgia Querin et al., 2015)​.

SBMA patients can display peculiar psychological characteristics including diffidence, marked emotional sensitivity and concentration problems ​(G. Querin et al., 2017)​. Soukup et al. reported systematic evidence of differing frontotemporal cognitive functioning in SBMA patients compared to age and education matched controls ​(Soukup et al., 2009)​. Despite similar intelligence per IQ assessment, SBMA patients were found to significantly underperform in a battery of neuropsychological tests. Interestingly, while this varied from mild to severe impairment and “astonishingly widespread”, most were subclinical in expression. Executive function and short- and long-term memory were found to be domains exhibiting pronounced deficits, while attentional control was also deficient. Consistent with prefrontal deficits, Di Rosa et al. utilised control matched neuropsychological testing, reporting a significant weakness in cognitive empathy but not in areas of affective empathy in SBMA patients. They suggest even mild impairment in mentalising may have profound implications for interpersonal relations, particularly when such changes are not recognized as the consequence of neural processes ​(Di Rosa et al., 2014)​. In a small cohort of SBMA patients, Romigi et al. reported a decrease in both subjective and objective sleep quality parameters compared with healthy age and sex matched controls. 77.8% of SBMA patients subjectively experienced disturbed sleep per the Pittsburgh Sleep Quality Index. Objectively, time in bed, total sleep time and sleep efficiency were significantly lower in SBMA patients, with a significantly higher apnea-hypopnea index. SBMA patients showed periodic limb movements. Obstructive sleep apnea was evident in a majority of patients, REM sleep without atonia was observed in 22% of patients ​(Romigi et al., 2014)​.

Although CAG repeat length is not held to be strictly associated with severity, individual case reports of patients with abnormally long CAG repeat lengths present with severe phenotypes that have expanded the clinical understanding of SBMA. Grunseich et al. reported a 29-year-old SBMA patient with a long 68 CAG repeat expansion. The patient experienced early onset of multisystemic symptoms. He had been born with penile congenital abnormality. He developed gynecomastia by 16 and muscle weakness, fatigue after exercise, fasciculations, cramping, and tremor by age 18. He experienced ejaculation difficulties, testicular atrophy, burning neuropathic pain and dysesthesia in the feet and fingertips, reduced sweating and decreased facial hair growth. Tongue atrophy was noted, and weakness was observed in the orbicularis oculi and orbicularis oris. He exhibited perioral fasciculations, severe limb weakness bilaterally, difficulty standing on his heels and ankles, and loss of temperature and vibratory sensation in the fingers and toes. Abnormalities were seen on muscle MRI. Evidence of autonomic dysfunction suggestive of small fiber dysfunction was determined, including negligible sweat responses and orthostatic tachycardia without blood pressure changes or symptoms ​(Grunseich et al., 2014)​. Similarly, Madeira et al., reported a phenotype of an exceptional 72 CAG repeat length. This man was 53 years old and underweight. He complained of shortness of breath, difficulty breathing while lying down and paroxysmal nocturnal dyspnea. He had a micropenis, small testicles and progressive testicular failure. Deep tendon reflexes were absent. Fasciculations, weakness and atrophy were apparent in the tongue, masseter muscles and limb muscles. Neck muscles were severely weakened. He had osteopenia, with low bone mass densities in the lumbar spine and femoral neck. He additionally had dyslipidaemia ​(Madeira et al., 2017)​. These phenotypical presentations highlight the broad effects associated with alteration of androgen-dependant signaling pathways.

Reliable biomarkers for SBMA remain a challenge ​(Manzano et al., 2018; Giorgia Querin et al., 2018)​, but common findings have been established. Creatine-Kinase will often be elevated ​(G. Querin et al., 2017)​. Testosterone, LH and FSH are generally found to be within normal bounds, although T and DHT can be high or low in some patients ​(Hashizume et al., 2012; Ni et al., 2015; Giorgia Querin et al., 2015; Rhodes et al., 2009)​. Patterns of androgen insensitivity per biomarkers are seen in some patients as per the Androgen Sensitivity Index, and have been reported to correlate positively with CAG repeats ​(Dejager et al., 2002; Giorgia Querin et al., 2015)​. High proportions of patients will show lipid and metabolic abnormality, including elevated total cholesterol, triglycerides, fasting glucose and insulin ​(Dejager et al., 2002; Francini-Pesenti et al., 2018; Guber et al., 2017; Giorgia Querin et al., 2015)​. Signs of non-alcoholic fatty liver disease including excess deposition of triacylglycerol in the liver have been reported as a near universal finding, even in patients with normal BMI ​(Guber et al., 2017)​. The observation that hepatic AR knockout models that develop steatosis and insulin resistance ​(Lin et al., 2008)​, as well as multisystem disruption of metabolic homeostasis, is suggestive of direct disease involvement in the observed NAFLD in SBMA patients. Serum hydroxyvitamin D was reported as low in a majority of patients in a large cohort ​(Giorgia Querin et al., 2015)​. Interestingly, the markers of neuronal damage phosphorylated neurofilament heavy chain and neurofilament light chain levels are not elevated in serum of SBMA patients or animal models and do not correlate with phenotypical severity ​(Lombardi, Bombaci, et al., 2019; Lombardi, Querin, et al., 2019)​.

Muscle involvement is diffuse. Myopathic evidence present upon muscle biopsy ​(Manzano et al., 2018)​ is supportive of a conserved pathological mechanism that likely underlies a vast proportion of clinical manifestations ​(Baniahmad, 2015; G. Querin et al., 2017)​. In a 40-patient cohort, muscle fat content was significantly higher than controls in the semitendinosus, semimembranosus, biceps femoris longus, triceps surae and spared sartorius, gracilis, biceps femoris brevis, and tibialis anterior. Affected leg muscles showed greater involvement than arm muscles, and muscle fat content correlated to muscle strength and function tests, disease duration and severity, and creatine kinase and testosterone levels ​(Dahlqvist et al., 2019)​. White matter alterations in the corticospinal tracts, limbic system, brainstem and cerebellum have been demonstrated via quantitative brain imaging ​(Kassubek et al., 2007; Unrath et al., 2010)​, while voxel based morphometry has identified gray matter atrophy in the frontal lobes and brainstem ​(Pieper et al., 2012)​. Skeletal muscle, known to be AR enriched, is a notable site of toxicity and tissue biopsy has demonstrated denervation, muscle fiber degeneration and myogenic changes in addition to neurogenic atrophy ​(Giorgia Querin et al., 2015; Sorarù et al., 2008)​. Somatosensory evoked potentials are regularly abnormal, while electromyography and nerve conduction study will often reveal low sensory nerve amplitudes, decreased compound motor action potentials and evidence of diffuse denervation ​(BUECKING, 2000; Kachi et al., 1992; Pennuto & Rinaldi, 2018; Polo et al., 1996)​. Broad involvement of sensory neurons and autonomic skin denervation were reported with abnormal sweat test results ​(Manganelli et al., 2007)​. These findings align with AR accumulation and degeneration in autonomic regions including the dorsal root ganglia ​(Antonini et al., 2000)​.

The mechanisms of PolyQ AR toxicity are yet to be fully elucidated but it appears that levels of AR expression are directly correlated to muscular atrophy ​(Manzano et al., 2018)​. Both testosterone or DHT binding to the polyQ AR and its subsequent translocation of the expanded protein to the nucleus is required for toxicity as demonstrated in vivo ​(Katsuno et al., 2002; Nedelsky et al., 2010; Takeyama et al., 2002)​ and in vitro ​(Becker et al., 2000; Darrington et al., 2002; Stenoien et al., 1999; Walcott & Merry, 2002)​. Higher androgen levels in males are therefore responsible for the symptomatic presentation, and female carriers will ordinarily remain asymptomatic ​(Chevalier-Larsen, 2004; Schmidt et al., 2002)​. In humans, exogenous androgen administration does not usually relieve clinical symptoms ​(Neuschmid-Kaspar et al., 1996)​ and has been reported to have reversibly worsened symptoms ​(Kinirons & Rouleau, 2008)​. Administrating testosterone to previously asymptomatic transgene SBMA female mice induces a distinct increase of symptoms similar to the level of untreated males, including progressive emaciation and motor dysfunction, pathological markers and nuclear localisation of pathogenic AR ​(Katsuno et al., 2002)​, demonstrating the androgen dependency of the pathology.

AR polyQ expansion involves a partial loss of the normal transcriptional activity of the AR ​(Chamberlain et al., 1994; Kazemi-Esfarjani et al., 1995; A. P. Lieberman, 2002; Mhatre et al., 1993)​ and this contributes to the pathology. However, neither loss of AR function nor androgen ablation is adequate for the pathology, and men with complete androgen insensitivity syndrome do not exhibit neurological symptoms ​(Chivet et al., 2019; Quigley et al., 1992)​. As such, the disease entails a proteotoxic gain of function ​(A. P. Lieberman, 2002; Manzano et al., 2018; Nath et al., 2018; Pennuto & Rinaldi, 2018)​. The mutant AR disrupts many downstream pathways, and alteration of diverse cellular processes including transcription, RNA splicing, axonal transport, ion homeostasis, and mitochondrial function likely coalesce to cause toxicity ​(Borgia et al., 2017; Chua et al., 2015; Eftekharzadeh et al., 2019; Malik et al., 2019)​. Diffuse nuclear accumulation of mutant AR is frequent and extensive in SBMA, occurring in a wide array of CNS nuclei and visceral organs ​(H. Adachi, 2005; Doi et al., 2013; Katsuno et al., 2002)​. Nuclear accumulation of AR is reported to be important to the pathology ​(Nedelsky et al., 2010)​. Animal models have revealed export of the pathogenic AR protein is impaired in the absence of any cell-wide disruption of nucleocytoplasmic transport ​(Arnold et al., 2019)​. Significant age, hormone and CAG repeat length dependent impairment of multiple ubiquitin-proteasome genes have been demonstrated to result from a toxic gain of AR function, progressively compounding toxicity through a failure of polyQ AR clearance. Diminished expression of numerous components of the ubiquitin-proteasome pathway including ubiquitin receptors, proteolytic subunits and assembly scaffold proteins were recently reported in skeletal muscle of AR113Q male mice. This involved significant reduction of ~30% of constitutive proteasome subunits and ~20% of E2 ubiquitin conjugating enzymes, with no upregulation observed and a non-significant trend towards reduced expression in many more subunits ​(Nath et al., 2018)​. This differentiates AR-mediated toxicity from skeletal muscle atrophy following cachexia, renal failure, surgical denervation, fasting, tumors, and diabetes, which all exhibit an up-regulation of proteasome subunits ​(Sacheck et al., 2006)​.

Using cell culture and animal models, androgen axis targeted therapeutic strategies have been explored. Androgen ablation and treatment with AR antagonists are beneficial and ameliorate the SBMA pathogenicity ​(Baniahmad, 2015)​, demonstrating phenotypical improvement beyond simply a slowing of the disease progression. The antiandrogen flutamide was protective of androgen-mediated toxicity across several SBMA models, preventing or reversing motor dysfunction of transgene models and extending the life of knock-in males significantly ​(Renier et al., 2014)​. Similarly, castration of AR97Q males dramatically prevented phenotypical presentation, with these mice showing significantly extended life, ameliorated muscle atrophy and body size reduction, virtually absent motor impairment, and markedly reduced nuclear AR staining intensities as compared to sham operated AR97Q mice displaying significant pathology ​(Katsuno et al., 2002)​. Castration was also remarkably effective in 112 and 113 glutamine models ​(Chevalier-Larsen, 2004; Nath et al., 2018)​. Leuprorelin has also been demonstrated as effective in transgenic mice ​(Katsuno et al., 2003)​. 14 years of prospective quantitative measurement of a single SBMA patient who underwent leuprolide acetate treatment for the initial 7 years before undergoing orchiectomy indicated that long term androgen deprivation slows disease progression when compared to existing control data ​(Hijikata et al., 2019)​. In transgenic mice, SBMA symptoms have been shown to be ameliorated through IGF-1 treatment or overexpression in muscle, which promotes AR degradation through phosphorylation by Akt ​(Palazzolo et al., 2009; Rinaldi et al., 2012)​. Treatment with genistein, an antiandrogenic soy isoflavone, was demonstrated to promote dissociation of the AR from the co-regulator ARA70 and attenuate pathology and improved survival in 97Q mouse models ​(Qiang et al., 2013)​. Modulation of activation function-2 of the AR with the compound MEPB rescued toxicity in a drosophila model of SBMA and showed a dose-dependent rescue from loss of body weight, rotarod activity and grip strength, neuronal loss, neurogenic atrophy and reversed testicular atrophy in a SBMA mouse model ​(Badders et al., 2018)​. It is likely that the new generation of Selective Androgen Receptor Degraders in development for use in castration resistant prostate cancer ​(Han et al., 2019; Ponnusamy et al., 2017)​ will be of interest with regard to a potential treatment for SBMA. ASC-J9, an AR degrader enhancer with structural similarity to curcumin ​(Cheng et al., 2018)​, has already been shown to rescue SBMA motor symptoms and improve sexual function in transgenic 97Q mice ​(Yang et al., 2007)​.

In cell models, targeting the heat shock protein families, molecular chaperones to the AR, suppresses aggregation and enhances polyQ AR degradation, making them a potential therapeutic target ​(Bailey, 2002)​. Mutant AR forms a Hsp90 chaperone complex preferentially compared to wild type AR, and use of a Hsp90 inhibitor, Tanespimycin, has been demonstrated to be effective at degrading polyQ AR in vitro and in vivo modelling, markedly ameliorating motor impairment ​(Waza et al., 2005)​. Tanespimycin, however, has broad interruptive effects and is not well tolerated ​(Yang et al., 2007)​, and Hsp90 inhibitors can induce the degradation of hundreds of client proteins that are likely needed for diverse processes ​(Eftekharzadeh et al., 2019)​. Recently, Eftekharzadeh et al. suggested that Hsp70 activation with small molecules such as JG-98 or JG-294 is a safer potential approach to leveraging protein quality control mechanisms to degrade the AR in SBMA and other androgen-mediated conditions ​(Eftekharzadeh et al., 2019)​. Hsp70 overexpression is similarly seen to significantly ameliorate SBMA symptoms in a transgenic mouse model by reducing the amount of nuclear-localized mutant AR protein ​(Hiroaki Adachi et al., 2003)​. Arimoclomol, a co-inducer of the heat shock response limited to stressed cells, has been observed to delay disease progression in a mouse model of SBMA through the prevention of motor neuron degeneration and alleviation of muscle atrophy ​(Rinaldi et al., 2015)​. Trehalose has been suggested as a potential therapeutic agent, and in vitro studies suggest beneficial effects resulting from increased autophagic clearance of the mutant AR ​(Cicardi et al., 2019)​. Sodium butyrate, a histone deacyletase inhibitor capable of modulating AR expression ​(Paskova et al., 2013)​, showed improvement in motor deficits and histopathological impairment of neurons and muscle within an narrow optimum dose window in transgenic mice ​(Minamiyama, 2004)​. Inhibition of Src kinase, a pathway upregulated by polyglutamine expansion and AR overexpression, has been demonstrated to mitigate toxicity in SBMA animal and cell models ​(Iida et al., 2019)​.

Given the significant advancement in the understanding of the pathological mechanisms, a move towards targeted molecular therapies addressing the systemic pathological processes is likely in the near future ​(Giorgia Querin et al., 2018)​. To achieve a disease modifying therapy for SBMA, Rinaldi et al. suggest a coordinated, collaborative effort of researchers with multiple areas of expertise, clinicians, the pharmaceutical industry and the involvement of patient groups ​(Rinaldi et al., 2015)​.

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