[Yips in Kyudo (Japanese archery): prevalence, classification, and aggravating factors].

In Kyudo (Japanese archery), there are four disorders that hinder an archer's performance: Hayake (releasing the bow too early), Motare (unable to release the bow when intended), Biku (jerking when aiming), and Yusuri (shaking when drawing the bow, or aiming). These disorders are similar to Yips, a psycho-neuromuscular movement disorder, recognized in various sports, but few studies have examined yips in Kyudo. This study examined the frequency, classification, and risk factors of yips in Kyudo among medical students. The results showed that 41 of 65 students (63.1%) experienced at least one disorder. The frequency of Hayake was the highest (35 patients; 85.3%). An experience of playing was associated with the increased risk of yips in Kyudo. Motare was the only disorder that appeared on its own, and without complications from other disorders. Based on its characteristics, it was suspected that task-specific focal dystonia involved in Motare.

Serial evaluation of swallowing function in a long-term survivor of V180I genetic Creutzfeldt-Jakob disease.

Swallowing function in long-term survivors with Creutzfeldt-Jakob disease (CJD) remains unknown. Herein, we demonstrated serial evaluation of swallowing function in a case with V180I genetic CJD (gCJD) using videofluoroscopic examination of swallowing (VF). A 69-year-old woman was admitted to our hospital because of bradykinesia and memory disturbances 4 months after the onset of symptoms. Neurological examination revealed dementia, bradykinesia and frontal signs. Diffusion-weighted MRI revealed bilateral cortical hyperintensity in the frontal, temporal, and parietal cortices, and PRNP gene analysis indicated a V180I mutation. Her dysphagia gradually progressed, and she received percutaneous gastrostomy 42 months after the onset. VF was performed at 27, 31, 39, and 79 months after the onset. Although bolus transport from oral cavity to pharynx gradually worsened and initiation of the pharyngeal swallow was gradually delayed, the pharyngeal swallowing function was preserved even at 72 months after onset. MRI revealed no apparent atrophy of brainstem, and single photon emission computed tomography showed preserved regional cerebral blood flow in the brainstem. These findings suggest that the pathophysiology of dysphagia in a long-term survivor of V180I gCJD is that of pseudobulbar palsy, likely owing to preserved brainstem function even in the akinetic mutism state.

Clinicopathological findings of a long-term survivor of V180I genetic Creutzfeldt-Jakob disease.

The clinical characteristics of genetic Creutzfeldt-Jakob disease (gCJD) with a V180I mutation in the PRNP gene (V180I gCJD) are unique: elderly-onset, gradual progression, sporadic fashion, and cortical oedematous hyper-intensity on diffusion-weighted MRI (DW-MRI). This phenotype may become a potential target of future clinical therapeutic trials. The average disease duration of V180I gCJD patients is 23-27 months; however, considerably long-term survivors are also reported. The factors influencing survival and the clinicopathological characteristics of long-term survivors remain unknown. Herein, we report clinicopathological findings of a long-term survivor of V180I gCJD. A 78-year old woman was admitted to our hospital due to dementia and left hand tremor approximately 1.5 months after symptom onset. Neurological examination revealed dementia, frontal signs, and left hand tremor at admission. She had no family history of dementia or other neurological disease. DW-MRI revealed cortical oedematous hyper-intensities in the bilateral frontal lobes and the right temporal and parietal lobes. PRNP gene analysis indicated a V180I mutation with methionine homozygosity at codon 129. The symptoms gradually progressed, and she died of aspiration pneumonia 61 months after symptom onset. Neuropathological examination revealed severe cerebral atrophy with moderate to severe gliosis, but the brainstem was well preserved. Various-sized and non-confluent vacuole type spongiform changes were extensively observed in the cerebral cortices. Prion protein (PrP) immunostaining revealed weak and synaptic-type PrP deposits in the cerebral cortices. We consider that long-term tube feeding, and very mild brainstem involvement may be associated with the long-term survival of our V180I gCJD patient.

Clinicopathological findings of an MM2-cortical-type sporadic Creutzfeldt-Jakob disease patient with cortical blindness during a course of glaucoma and age-related macular degeneration.

Here, we report an autopsy-verified patient with MM2-coritical-type sporadic Creutzfeldt-Jakob disease (MM2C-type sCJD) presenting cortical blindness during a course of glaucoma and age-related macular degeneration, and focus on the difficulties involved in early clinical diagnosis. An 83-year-old man was admitted to our hospital 15 months after the onset of cortical blindness, and 9 months after the onset of progressive dementia. Neurological examination revealed dementia, frontal signs, visual disturbance, dysphagia, myoclonus and exaggerated tendon reflexes in the four extremities. Diffusion-weighted MRI (DW-MRI) showed cortical hyperintensities predominantly in the bilateral occipital lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129. Cerebrospinal fluid (CSF) examination revealed elevation of 14-3-3 and total tau protein. The symptoms progressed gradually, and the patient died of aspiration pneumonia, 30 months after the onset. Neuropathological examination revealed extensive large confluent vacuole-type spongiform changes in the cerebral cortices. Prion protein (PrP) immunostaining showed perivascular and plaque-type PrP deposits. We diagnosed our patient as MM2C-type sCJD. There are two difficulties in the early clinical diagnosis of MM2C-type sCJD with ocular disease in the elderly; delayed utilization of DW-MRI, and accompaniment of ocular disease. For early diagnosis of MM2C-type sCJD, we conclude that clinician should perform DW-MRI for patients with isolated dementia or cortical visual disturbance.

Comprehensive Tool to Assess Oral Feeding Support for Functional Recovery in Post-acute Rehabilitation.

OBJECTIVE: To determine the influence of the Kuchi-kara Taberu (KT) index on rehabilitation outcomes during hospitalized convalescent rehabilitation. DESIGN: A historical controlled study. SETTING AND PARTICIPANTS: A rehabilitation hospital. PARTICIPANTS: Patients who were admitted to a convalescent rehabilitation ward from June 2014 to May 2017. MEASURES: Patients' background characteristics included age, sex, nutritional status, activities of daily living (ADL) assessed using the Functional Impedance Measure (FIM), dysphagia assessed using the Functional Oral Intake Scale (FOIS), and reasons for rehabilitation. The following values before (control group) and after initiation of the KT index intervention period (intervention group) were compared: gain of FIM, length of stay, accumulated rehabilitation time, discharge destination, gain of FOIS, gain of body weight (BW), and nutritional intake (energy and protein). RESULTS: Mean age was 76.4 ± 12.3 years (n = 233). There were no significant differences in the baseline characteristics of the patients at admission between the control and intervention groups, except for reason of rehabilitation. The intervention group demonstrated statistically higher values for the total (P = .004) and motor FIM gain (P = .003), total (P = .018) and motor FIM efficiency (P = .016), and FOIS gain (P < .001), compared with values in the control group. The proportion of patients returning home was statistically more frequent in the intervention group compared with that in the control group (73.4% vs 85.5%, odds ratio 2.135, 95% confidence interval [CI] 1.108-4.113, P = .022). Multivariate analyses indicated that intervention using the KT index was a significant independent factor for increased FIM gain (ß coefficient = 0.163, 95% CI 1.379-8.329, P = .006) and returning home (adjusted odds ratio 2.570, 95% CI 1.154-5.724, P = .021). CONCLUSIONS/IMPLICATIONS: A rehabilitation program using the KT index may lead to improvement of inpatient outcomes in post-acute care. Further prospective research is warranted to confirm the efficacy of this program.

dnc-1/dynactin 1 knockdown disrupts transport of autophagosomes and induces motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.

Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-beta signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-beta signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-beta receptor type II (TbetaRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TbetaRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-beta due to the transcriptional dysregulation of TbetaRII is associated with polyglutamine-induced motor neuron damage in SBMA.

[Exploration of pathogenesis and therapy development for ALS employing sporadic disease model].

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain poorly understood even now 140 years after the first description of the disease in 1869 by Jean-Martin Charcot. Exploration of pathogenesis of ALS has long been dependent on transgenic animal models with mutations in the copper/ zinc superoxide dismutase 1 (SOD1) gene. However, the lack of therapeutic concordance between these animal models and human sporadic ALS patients is troubling. The reasons include that there might exist the differences of pathogenesis between sporadic and familial ALS and/or the disease models for sporadic ALS have not been established. We have been working on screening motor neuron-specific genes critical for pathogenesis of sporadic ALS using cDNA microarray and laser capture microdissection techniques. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of sporadic ALS. In particular, dynactin-1, a major component of dynein/dynactin complex and several cell cycle-related genes are the targets of our research. Development and analysis of new disease models for sporadic ALS based on these genes will open an avenue for novel therapeutics.

Heat shock proteins in neurodegenerative diseases: pathogenic roles and therapeutic implications.

Neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathological hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs has been reported to reduce the number and size of inclusions and accumulation of disease-causing proteins, and ameliorate the phenotypes in neuronal cell and mouse models. Hsp90 inhibitors also exert therapeutic effects through selective proteasome degradation of its client proteins. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and HSP inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases.

TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases.

The 43-kDa TAR DNA-binding protein (TDP-43) is known to be a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Although TDP-43 is a nuclear protein, it disappears from the nucleus of affected neurons and glial cells, implicating TDP-43 loss of function in the pathogenesis of neurodegeneration. Here we show that the knockdown of TDP-43 in differentiated Neuro-2a cells inhibited neurite outgrowth and induced cell death. In knockdown cells, the Rho family members RhoA, Rac1, and Cdc42 GTPases were inactivated, and membrane localization of these molecules was reduced. In addition, TDP-43 depletion significantly suppressed protein geranylgeranylation, a key regulating factor of Rho family activity and intracellular localization. In contrast, overexpression of TDP-43 mitigated the cellular damage caused by pharmacological inhibition of geranylgeranylation. Furthermore administration of geranylgeranyl pyrophosphate partially restored cell viability and neurite outgrowth in TDP-43 knockdown cells. In summary, our data suggest that TDP-43 plays a key role in the maintenance of neuronal cell morphology and survival possibly through protein geranylgeranylation of Rho family GTPases.

Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA. METHODS: Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474). RESULTS: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem. INTERPRETATION: These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.

17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse.

The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.

[Exploration of pathogenesis-associated molecules and development of disease models for sporadic ALS].

The mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS and by the development and analysis of mutant SOD1 transgenic animal models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of SALS. Of these, in this paper, we will focus on Dorfin, a RING finger-type E3 ubiquitin ligase and dynactin1, a major component of dynein/dynactin complex that is important for retrograde axonal transport. We are now challenging creation of the disease models by simulating the gene expression changes specifically observed in SALS patients.

CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.

Gene expression profiling toward understanding of ALS pathogenesis.

Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. To approach genes causative or critical for ALS, gene expression profiling in tissues primarily affected by the disease has represented an attractive research strategy. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of ALS. However, we have barely arrived at the starting point and are confronting an enormous number of genes whose roles remain undetermined. Challenging tasks lie ahead of us such as identifying which genes are really causative for ALS and developing a disease model of SALS with due consideration for the expression changes in those genes.

Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG).

Heat shock proteins (HSPs) that function mainly as molecular chaperones play an important role in the folding and quality control of proteins. Compared with these chaperones, Hsp90 is unique in that it binds to substrate proteins, called Hsp90 client proteins. Hsp90 is involved in the folding, activation, and assembly of its client proteins in association with its co-chaperones. Because numerous oncoproteins belonging to the Hsp90 client protein family are selectively degraded by Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG), a first-in-class Hsp90 inhibitor, is now under clinical trials as a novel molecular-targeted agent for a wide range of malignancies. In spinal and bulbar muscular atrophy (SBMA), the pathogenic gene product is polyglutamine (polyQ)-expanded androgen receptor (AR), which belongs to the Hsp90 client protein family and is known to be degraded by 17-AAG. We have recently demonstrated that administration of an anticancer agent 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. The ability of 17-AAG to degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach using a novel anticancer agent 17-AAG has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases.

Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.

Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.

Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the first exon of the androgen receptor gene (AR). The pathogenic, polyglutamine-expanded AR protein accumulates in the cell nucleus in a ligand-dependent manner and inhibits transcription by interfering with transcriptional factors and coactivators. Heat-shock proteins (HSPs) are stress-induced chaperones that facilitate the refolding and, thus, the degradation of abnormal proteins. Geranylgeranylacetone (GGA), a nontoxic antiulcer drug, has been shown to potently induce HSP expression in various tissues, including the central nervous system. In a cell model of SBMA, GGA increased the levels of Hsp70, Hsp90, and Hsp105 and inhibited cell death and the accumulation of pathogenic AR. Oral administration of GGA also up-regulated the expression of HSPs in the central nervous system of SBMA-transgenic mice and suppressed nuclear accumulation of the pathogenic AR protein, resulting in amelioration of polyglutamine-dependent neuromuscular phenotypes. These observations suggest that, although a high dose appears to be needed for clinical effects, oral GGA administration is a safe and promising therapeutic candidate for polyglutamine-mediated neurodegenerative diseases, including SBMA.