Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson's disease and L-Dopa induced dyskinesia.
Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson's disease and L-Dopa induced dyskinesia.
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DOI：
10.1038/s42003-021-02567-3
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发表时间：
2021-09-22
影响因子：
5.9
通讯作者：
Kottmann AH
中科院分区：
文献类型：
--
作者：
Malave L;Zuelke DR;Uribe-Cano S;Starikov L;Rebholz H;Friedman E;Qin C;Li Q;Bezard E;Kottmann AH
左旋多巴诱发的运动障碍（LID）是帕金森病多巴胺替代疗法的一种使人衰弱的副作用。LID的机械基础仍然模糊不清。在这里，我们报告说，减少音刺猬（Shh）信号在基底神经节引起的中脑多巴胺神经元的变性促进LID的形成和表达。我们发现Smoothened的药理学激活，Shh的下游效应子，在帕金森病的神经毒性6-OHDA和遗传性无晶状体小鼠模型中减弱LID。采用条件性遗传功能丧失的方法，我们表明，减少多巴胺神经元的Shh分泌或胆碱能中间神经元的Smoothened活性促进LID。相反，胆碱能中间神经元中组成型活性Smoothened的选择性表达足以使帕金森病的致敏无晶状体模型对LID具有抗性。此外，在其他方面完整的小鼠中，在没有L-多巴的情况下，通过长时间的光遗传学刺激从多巴胺神经元中急性耗尽Shh，产生LID样不自主运动。这些发现表明，增强L-Dopa治疗的大脑中的Shh信号传导可能是一种有前途的治疗方法，用于减轻L-Dopa长期治疗的运动障碍副作用。Lauren Malave等人研究了L-Dopa诱导的运动障碍（LID）动物模型中背侧纹状体中sonic hedgehog信号传导的影响。他们的研究结果表明，增加音刺猬信号可以降低LID和异常不自主运动的严重程度，这表明未来的治疗方法可以减轻L-Dopa长期治疗的运动障碍合并症。
L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson’s Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID. We find that the pharmacological activation of Smoothened, a downstream effector of Shh, attenuates LID in the neurotoxic 6-OHDA- and genetic aphakia mouse models of Parkinson’s Disease. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from dopamine neurons or Smoothened activity in cholinergic interneurons promotes LID. Conversely, the selective expression of constitutively active Smoothened in cholinergic interneurons is sufficient to render the sensitized aphakia model of Parkinson’s Disease resistant to LID. Furthermore, acute depletion of Shh from dopamine neurons through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa. Lauren Malave et al. examine the impact of sonic hedgehog signaling in the dorsal striatum in L-Dopa induced dyskinesia (LID) animal models. Their results suggest that increasing sonic hedgehog signaling can reduce the severity of LID and abnormal involuntary movements, suggesting future therapeutic approaches to mitigate dyskinetic comorbidities of long-term treatment with L-Dopa.
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影响因子：
16.2
作者：
Chuhma N;Mingote S;Moore H;Rayport S
通讯作者：
Rayport S
影响因子：
13.8
作者：
Arensdorf AM;Marada S;Ogden SK
通讯作者：
Ogden SK
影响因子：
8.8
作者：
Arensdorf AM;Dillard ME;Menke JM;Frank MW;Rock CO;Ogden SK
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Ogden SK
影响因子：
6.1
作者：
DAWSON, VL;DAWSON, TM;WAMSLEY, JK
通讯作者：
WAMSLEY, JK
影响因子：
5.3
作者：
Alcacer, Cristina;Santini, Emanuela;Herve, Denis
通讯作者：
Herve, Denis