Pharmacological enhancement of retinoid-related orphan receptor α function mitigates spinocerebellar ataxia type 3 pathology

Watanave, Masashi; Hoshino, Chiaki; Konno, Ayumu; Fukuzaki, Yumi; Matsuzaki, Yasunori; Ishitani, Tohru; Hirai, Hirokazu

doi:10.1016/j.nbd.2018.10.014

Cited by 20 publications

(8 citation statements)

References 47 publications

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“…In line with findings from staggerer mice and SCA1 mice, transgenic models of SCA3 also display reduced expression of RORα ( Konno et al, 2014 ). Whilst the ataxin-1 protein is found to directly interact with RORα and forming protein complexes ( Serra et al, 2006 ), the ataxin-3 protein does not directly bind with RORα ( Watanave et al, 2019 ), suggesting divergent underlying pathogenic mechanisms.…”

Section: What Pathophysiological Changes Within the Cerebellum Underlmentioning

confidence: 99%

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

2020

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The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that share convergent disease features. A common symptom of these diseases is development of ataxia, involving impaired balance and motor coordination, usually stemming from cerebellar dysfunction and neurodegeneration. For most spinocerebellar ataxias, pathology can be attributed to an underlying gene mutation and the impaired function of the encoded protein through loss or gain-of-function effects. Strikingly, despite vast heterogeneity in the structure and function of disease-causing genes across the SCAs and the cellular processes affected, the downstream effects have considerable overlap, including alterations in cerebellar circuitry. Interestingly, aberrant function and degeneration of Purkinje cells, the major output neuronal population present within the cerebellum, precedes abnormalities in other neuronal populations within many SCAs, suggesting that Purkinje cells have increased vulnerability to cellular perturbations. Factors that are known to contribute to perturbed Purkinje cell function in spinocerebellar ataxias include altered gene expression resulting in altered expression or functionality of proteins and channels that modulate membrane potential, downstream impairments in intracellular calcium homeostasis and changes in glutamatergic input received from synapsing climbing or parallel fibers. This review will explore this enhanced vulnerability and the aberrant cerebellar circuitry linked with it in many forms of SCA. It is critical to understand why Purkinje cells are vulnerable to such insults and what overlapping pathogenic mechanisms are occurring across multiple SCAs, despite different underlying genetic mutations. Enhanced understanding of disease mechanisms will facilitate the development of treatments to prevent or slow progression of the underlying neurodegenerative processes, cerebellar atrophy and ataxic symptoms.

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Section: What Pathophysiological Changes Within the Cerebellum Underlmentioning

confidence: 99%

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

2020

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“…Retinoid-related orphan receptor α (RORα), a type 1 metabotropic glutamate receptor signaling molecule [109], sustains PC dendritic complexity and mono-innervation by climbing fibers [110]. Decreased RORα expression was detected in the nuclei of SCA3 mouse PCs [109,111], and single injection of the RORα/γ agonist SR1078 rescued the behavioral, morphological, and functional deficits in these SCA3 model mice [111].…”

Section: Glutamate Receptor Signalingmentioning

confidence: 99%

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Chen

Hong

Lin

et al. 2020

IJMS

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Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function.

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“…SR1078 was identified as the first synthetic RORα/γ agonist which modulated the conformation of RORγ and activates RORα‐ and RORγ‐driven transcription [25]. SR1078 has shown protective effects against a variety of diseases in mouse models, including autism [26], allergic asthma [27], liver cancer [28], liver fibrosis [29], renal ischaemia/reperfusion injury [30], rheumatoid arthritis [31], diabetic cardiomyopathy [32], neuroblastoma [21] and Machado‐Joseph disease [33]. Although SR1078 elicited such diverse benefits and effectively enhanced BMAL1 expression, SR1078 treatment failed to counteract cartilage degeneration in our study.…”

Section: Discussionmentioning

confidence: 99%

Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

Pang

Wang

et al. 2022

The FEBS Journal

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Dampened peripheral clocks have been linked to osteoarthritis (OA), yet it is unclear whether drugging the clock can ameliorate OA. Given that RORs and REV-ERBs mediate respectively, positive and negative transcriptional feedback of the master clock gene BMAL1, we investigate whether RORs agonist Nobiletin (NOB) and SR1078, and REV-ERBs antagonist SR8278 can enhance BMAL1 expression and attenuate cartilage degeneration. NOB and SR8278 promoted BMAL1 expression and elicited mitigating effects against IL-1β-induced degeneration of cartilage explants, as evidenced by increased cellular density and collagen synthesis along with alleviated catabolism and collagen denaturation. Despite promoted BMAL1 expression, SR1078 concomitantly suppressed chondrocyte anabolism and catabolism. Consistent with these findings, NOB and SR8278 treatment, but not SR1078, effectively attenuated structural destruction of articular cartilage in surgery-induced OA mouse models. Notably, the beneficial effects of NOB and SR8278 were evidently observed in IL-1βinduced degeneration of human cartilage explants and immortalized human chondrocytes. Moreover, BMAL1 knockdown assays indicated that NOB and SR8278 enhanced clock function and concordantly rendered protection against altered anabolism and catabolism in a BMAL1-dependent regime. Collectively, our study suggests that targeting RORs and REV-ERBs to promote the dampened peripheral clocks could be a route taken to apply chronotherapy within the context of OA.

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Pharmacological enhancement of retinoid-related orphan receptor α function mitigates spinocerebellar ataxia type 3 pathology

Cited by 20 publications

References 47 publications

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

Aberrant Cerebellar Circuitry in the Spinocerebellar Ataxias

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

Drugging the circadian clock feedback cycle to ameliorate cartilage degeneration

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