Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy

Ogura, Yosuke; Sahashi, Kentaro; Hirunagi, Tomoki; Iida, Madoka; Miyata, Takaki; Katsuno, Masahisa

doi:10.1038/s41419-022-05001-6

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…We first showed that DHT treatment inhibited neurite outgrowth in the presence of polyQ-expanded AR, independent of its transcriptional ability at AREs, while hormone had no effect on neurite outgrowth in the presence of wild-type AR. The inhibition of polyQ-expanded AR on neurite outgrowth is consistent with previous findings of reduced axonogenesis in spinal cord slice cultures from SBMA mice ( 50 ). The lack of growth-enhancing effect of DHT in the presence of normal polyQ-length AR, however, seemingly contradicts prior studies ( 24 , 25 , 51 , 52 ).…”

Section: Discussionsupporting

confidence: 91%

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

Karliner,

Liu,

Merry

2024

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

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Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG trinucleotide repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (ARE). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker β-III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a pathway implicated in this pathology. These findings suggest that in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington’s disease and spinocerebellar ataxias.

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Section: Discussionsupporting

confidence: 91%

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

Karliner,

Liu,

Merry

2024

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

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“…Previously published microarray data on Gene Expression Omnibus, GSE39865 25 , was normalized using Robust Multichip Analysis of Bioconductor based on R (https://www.rproject.org), as previously described 15 . The resultant data was subjected to the GAGE analysis and WGCNA using iDEP.96 (http://bioinformatics.sdstate.edu/idep96/) 54 .…”

Section: Analysis Of Microarray Datamentioning

confidence: 99%

“…These studies suggest that polyQ-expanded AR induces transcriptional dysregulation in the early developmental stage. Recently, we have addressed impaired axonal outgrowth of motor neurons in the slice culture of embryonic spinal cord of a transgenic mouse model (AR-97Q) 15 , suggesting the neurotoxicity due to early androgen exposure during developmental stages. These findings prompted us to further investigate the effects of polyQ-expanded AR at the very early, preclinical stage in SBMA, in consideration of the following facts: first, circulating testosterone levels transiently increase immediately after birth to the similar levels in adulthood in rodents and human 16,17 ; second, this neonatal testosterone surge coincides with neurodevelopment events including synaptogenesis, gliogenesis, and synaptic pruning 18 , which determines morphological and physiological properties of motor neurons 19,20 .…”

Section: Introductionmentioning

confidence: 99%

Restoration of early postnatal synaptic dysregulation rescues polyglutamine-mediated motor neuron degeneration in mice

Katsuno,

Hirunagi,

Sahashi

et al. 2024

Preprint

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Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant up-regulation of glutamatergic synaptic genes, mediated by a master transcriptional repressor, Rest, during early postnatal development in a mouse model of SBMA. Further analysis indicates that the up-regulation of Rest-target synaptic genes is caused by an increased expression of Rest4, a neuron-specific isoform of Rest that derepresses the promoter activity of Rest-binding lesions. In addition, calcium imaging shows that induced pluripotent stem cell-derived motor neurons expressing polyglutamine-expanded AR are hyperexcitable compared to those expressing wild-type AR. Reducing neonatal AR or switching Rest4 to Rest using antisense oligonucleotides attenuates the up-regulation of the synaptic genes and ameliorates the disease phenotype and histopathology in SBMA mice. The late-onset neurodegeneration in SBMA is attributable to the synaptic defects and resulting hyperexcitability of motor neurons at early postnatal stages, which would be therapeutically targeted.

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“…Loss-of-function mutations of Mid1 cause Opitz G/BBB syndrome in humans. Additionally, it has been reported to have involvement in the pathology of asthma, cancer, and neurodegenerative diseases [18][19][20]. However, its implication in autoimmune disease has not been extensively studied [21,22].…”

Section: Introductionmentioning

confidence: 99%

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

Wei,

Li,

Huang

et al. 2024

Theranostics

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Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS). While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease. Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Methods: Mid1 -/- mice were generated by Crispr-Cas9 technology. T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1 -/- T cells into lymphocyte deficient Rag2 -/- mice. Mice were either immunized with MOG 35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE. In vitro Transwell ® assay or in vivo footpad injection were used to assess the migration of T cells. Results: Mid1 was significantly increased in the spinal cord of wild-type ( Wt ) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE. Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1 -/- mice after EAE induction. Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1 -/- mice. Mice that were adoptively transferred with pathogenic Mid1 -/- T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord. Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro . RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1 -/- mice, including mTOR signaling that plays a critical role in cell migration. Subsequent experiments confirmed the interaction between Mid1 and mTOR. Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration. In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion: Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS. ...

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Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy

Cited by 6 publications

References 43 publications

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA

Restoration of early postnatal synaptic dysregulation rescues polyglutamine-mediated motor neuron degeneration in mice

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

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