Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism

Horimoto, Yoshihiko; Hayashi, Emi; Ito, Yoshihiro; Iida, Akihiko; Goto, Yoji; Kato, Soushi; Okita, Kenji; Kako, Tetsuharu; Sato, Chikako; Tajima, Tomoyuki; Inagaki, Aki; Nokura, Kazuya; Hibino, Hiroaki; Matsukawa, Noriyuki; Yamada, Kazuo; Kabasawa, Hidehiro

doi:10.1007/s00415-020-09908-y

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…For example, HD and SCA1 patients can be clinically affected prior to any observed neurodegeneration [151][152][153][154][155][156] . Recent findings reveal that while the cerebellum degenerates early in SCA1, the striatum does degenerate later and more rapidly (with detectable changes in less than a year) later in the disease course.…”

Section: Discussionmentioning

confidence: 99%

“…However, an apparent absence of correlation between instability and disease relies upon disease being solely due to neurodegeneration, which it is not. For example, HD and SCA1 patients can be clinically affected prior to any observed neurodegeneration 151–156 . Recent findings reveal that while the cerebellum degenerates early in SCA1, the striatum does degenerate later and more rapidly (with detectable changes in less than a year) later in the disease course.…”

Section: Discussionmentioning

confidence: 99%

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Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

Gall-Duncan

Luo

Jurkovic

et al. 2022

Preprint

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Tandem CAG repeat expansion mutations cause >15 neurodegenerative diseases, where ongoing expansions in patients brains are thought to drive disease onset and progression. Repeat length mutations will involve single-stranded DNAs prone to form mutagenic DNA structures. However, the involvement of single-stranded DNA binding proteins (SSBs) in the prevention or formation of repeat instability is poorly understood. Here, we assessed the role of two SSBs, canonical RPA (RPA1-RPA2-RPA3) and the related Alternative-RPA (Alt-RPA, RPA1-RPA4-RPA3), where the primate-specific RPA4 replaces RPA2. RPA is essential for all forms of DNA metabolism, while Alt-RPA has undefined functions. RPA and Alt-RPA are upregulated 2- and 10-fold, respectively, in brains of Huntington disease (HD) and spinocerebellar ataxia type 1 (SCA1) patients. Correct repair of slipped-CAG DNA structures, intermediates of expansion mutations, is enhanced by RPA, but blocked by Alt-RPA. Slipped-DNAs are bound and melted more efficiently by RPA than by Alt-RPA. Removal of excess slipped-DNAs by FAN1 nuclease is enhanced by RPA, but blocked by Alt-RPA. Protein-protein interactomes (BioID) reveal unique and shared partners of RPA and Alt-RPA, including proteins involved in CAG instability and known modifiers of HD and SCA1 disease. RPA overexpression inhibits rampant CAG expansions in SCA1 mouse brains, coinciding with improved neuron morphology and rescued motor phenotypes. Thus, SSBs are involved in repeat length mutations, where Alt-RPA antagonistically blocks RPA from suppressing CAG expansions and hence pathogenesis. The processing of repeat length mutations is one example by which an Alt-RPA-RPA antagonistic interaction can affect outcomes, illuminating questions as to which of the many processes mediated by canonical RPA may also be modulated by Alt-RPA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

Gall-Duncan

Luo

Jurkovic

et al. 2022

Preprint

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“…The dorsal striatum controls involuntary movements, and functional deficits accompanied by decreased DA levels in the striatum lead to the development of Parkinson's disease 25,26 . Patients with specific types of SCD have impaired function of dopaminergic nerves projecting to the striatum, with or without the development of Parkinsonism 27−29 . Taltirelin improves motor function in a rat model of Parkinson's disease via a sustained dopamine stimulating effect 30 .…”

Section: Discussionmentioning

confidence: 99%

Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside‐induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission

Ijiro

Yaguchi

Yokoyama

et al. 2022

Clin Exp Pharma Physio

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Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats.Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dosedependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.

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“…Tremor on orthostatism in a SCA3 patient showed improvement with clonazepam, trihexyphenidyl, and markedly with rotigotine patch [ 35 ]. Dysfunction of the nigrostriatal dopaminergic system has been demonstrated in SCAs using functional neuroimaging [ 31 33 35 36 153 154 ]. This might explain the beneficial role of levodopa.…”

Section: Management Of Tremor In Scamentioning

confidence: 99%

Tremor in Spinocerebellar Ataxia: A Scoping Review

Mukherjee,

Pandey

2024

Tremor and Other Hyperkinetic Movements

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Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism

Cited by 5 publications

References 24 publications

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside‐induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission

Tremor in Spinocerebellar Ataxia: A Scoping Review

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