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Unraveling dystonia circuitry in rodent models using novel neuromodulation techniques 利用新型神经调控技术揭示啮齿动物模型中的肌张力障碍回路

Dystonia

Pub Date : 2024-02-19 DOI: 10.3389/dyst.2024.11793

L. Rauschenberger, Chi Wang Ip

Dystonia is a network disorder presumed to result from abnormalities in multiple brain regions and in multiple cell populations. The specific pathomechanisms affecting the motor circuits in dystonia are, however, still largely unclear. Animal models for dystonia have long been used to advance our understanding on how specific brain regions and cell populations are involved in dystonia symptomatogenesis. Lesioning, pharmacological modulation and electrical stimulation paradigms were able to highlight that both the basal ganglia and the cerebellum are pathologically altered in these animal models for dystonia. Techniques such as optogenetics and chemogenetics now offer the opportunity for targeted modulation of brain regions and most importantly cell populations and circuits. This could not only allow for a better understanding of the dystonic brain, but potentially improve and expand treatment options. In hopes that the insights from these neuromodulation techniques will eventually translate into therapies, we aim to summarize and critically discuss the findings from different in vivo approaches used to dissect the network dysfunctions underlying dystonia.

肌张力障碍是一种网络性疾病，据推测是由多个脑区和多个细胞群的异常造成的。然而，影响肌张力障碍运动回路的具体病理机制在很大程度上仍不清楚。长期以来，肌张力障碍动物模型一直被用于加深我们对特定脑区和细胞群如何参与肌张力障碍症状发生的了解。病损、药理调节和电刺激范式能够突出显示，在这些肌张力障碍动物模型中，基底节和小脑都发生了病理改变。现在，光遗传学和化学遗传学等技术为有针对性地调节大脑区域以及最重要的细胞群和回路提供了机会。这不仅能更好地了解肌张力障碍大脑，还有可能改善和扩大治疗方案。我们希望从这些神经调控技术中获得的洞察力最终能转化为治疗方法，我们旨在总结并批判性地讨论用于剖析肌张力障碍基础网络功能障碍的不同体内方法的发现。

引用次数: 0

Clinical and physiological characteristics of tremor in a large cohort of focal and segmental dystonia. 一大群局灶性和节段性肌张力障碍患者震颤的临床和生理特征。

Dystonia

Pub Date : 2024-01-01 Epub Date: 2024-10-09 DOI: 10.3389/dyst.2024.12551

Zakia Jabarkheel, Aparna Wagle Shukla

Objective: Tremor is a frequent co-occurring feature in patients with dystonia, especially in focal and segmental dystonia. Clinical studies have shown that tremor is more commonly observed when dystonia spreads to contiguous body regions. However, there is insufficient characterization of tremor physiology in focal and segmental forms of dystonia. We aimed to ascertain the characteristics of tremor presenting in these specific subtypes.

Methods: We enrolled dystonia patients with head and arm tremors presenting to our center. We categorized these participants as focal and segmental dystonia following the Movement Disorders Society guidelines. We recorded the frequency, amplitude, rhythmicity, burst duration, and discharge pattern on accelerometer and electromyography recordings. We compared the physiology of tremors in focal vs. segmental dystonia. We determined whether the physiology was affected by clinical features such as demographics, age at onset, dystonia duration, alcohol responsiveness, family history, and botulinum toxin responsiveness.

Results: 72 patients, mainly focal cervical dystonia and focal cervical + arm or cranial dystonia (segmental) were enrolled. In the analysis of the head tremor recordings (n = 66; frequency range 3-6.5 Hz), we found that focal vs. segmental dystonia comparisons revealed a significantly lower frequency (mean ± standard deviation; 4.0 ± 0.9 Hz vs. 4.7 ± 1.0 Hz; p = 0.02), lower amplitude (0.004 ± 0.008 g²/Hz vs. 0.006 ± 0.008 g²/Hz; p = 0.03) and longer muscle burst durations (111.1 ± 40.4 ms vs. 91.5 ± 24 ms; p = 0.04). In the analysis of arm tremor recordings (n = 31; frequency range 3.5-7 Hz), we found focal vs. segmental dystonia comparison revealed a lower amplitude (0.04 ± 0.07 g²/Hz vs. 0.06 ± 0.06 g²/Hz; p = 0.045). In the stepwise regression analysis, the age at evaluation (β - 0.44; p = 0.006) and age at onset (β - 0.61; p = 0.005) significantly predicted the head tremor frequency whereas the alcohol responsiveness tended to predict the amplitude of the head tremor (β - 0.5; p = 0.04) and the arm tremor (β - 0.6; p = 0.02).

Conclusion: Our study found that the physiological characteristics of tremor in focal and segmental dystonia are somewhat distinct, suggesting that the spread of dystonia symptoms from one body region to another may have a bearing on the physiology of co-occurring tremor. The frequency of head tremors in younger participants was observed to be higher compared to older participants. The head and arm tremor tended be less severe in patients reporting alcohol responsiveness.

目的：震颤是肌张力障碍患者常见的共同症状，尤其是局灶性和节段性肌张力障碍。临床研究表明，当肌张力障碍扩散到相邻的身体区域时，更常观察到震颤。然而，对局灶性和节段性肌张力障碍的震颤生理特征描述不足。我们的目的是确定这些特定亚型的震颤特征。方法：我们招募了到我们中心就诊的头部和手臂震颤的肌张力障碍患者。我们按照运动障碍协会的指南将这些参与者分为局灶性和节段性肌张力障碍。我们在加速计和肌电图上记录了频率、振幅、节律性、爆发持续时间和放电模式。我们比较了局灶性肌张力障碍和节段性肌张力障碍的震颤生理学。我们确定生理是否受到临床特征的影响，如人口统计学、发病年龄、肌张力障碍持续时间、酒精反应性、家族史和肉毒杆菌毒素反应性。结果：纳入72例患者，主要为局灶性颈肌张力障碍和局灶性颈+臂或颅肌张力障碍（节段性）。在分析头震颤记录时(n = 66；频率范围3-6.5 Hz)，我们发现局灶性肌张力障碍与节段性肌张力障碍的比较显示频率明显较低(平均值±标准差；4.0±0.9 Hz vs. 4.7±1.0 Hz；p = 0.02)，幅值较低(0.004±0.008 g2/Hz vs. 0.006±0.008 g2/Hz；P = 0.03)和更长的肌肉爆发持续时间(111.1±40.4 ms比91.5±24 ms；P = 0.04)。在分析手臂震颤记录时(n = 31；频率范围为3.5-7 Hz)，我们发现局灶性肌张力障碍与节段性肌张力障碍的幅度较低(0.04±0.07 g2/Hz vs 0.06±0.06 g2/Hz；P = 0.045)。在逐步回归分析中，评价年龄(β - 0.44；P = 0.006)和发病年龄(β - 0.61；P = 0.005)显著预测头震颤频率，而酒精反应倾向于预测头震颤幅度(β - 0.5；P = 0.04)和手臂震颤(β - 0.6；P = 0.02)。结论：本研究发现局灶性肌张力障碍和节段性肌张力障碍震颤的生理特征有所不同，提示肌张力障碍症状从一个身体区域扩散到另一个身体区域可能与同时发生震颤的生理有关。年轻参与者的头部震颤频率被观察到比年长参与者高。报告酒精反应的患者头部和手臂震颤往往不那么严重。

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引用次数: 0

Piecing together a complex puzzle: 5 key challenges in basic dystonia research 拼凑复杂的拼图：肌张力障碍基础研究的五大挑战

Dystonia

Pub Date : 2023-12-21 DOI: 10.3389/dyst.2023.11615

M. Scarduzio, David G. Standaert

Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. Dystonia has a broad clinical spectrum and can affect different body regions, causing significant disability and reduced quality of life. Despite significant progress in understanding the disorder, many challenges in dystonia research remain. This mini-review aims to highlight the major challenges facing basic and translational research in this field, including 1) heterogeneity of the disorder, 2) limited understanding of its pathophysiology, 3) complications of using animal models, 4) lack of a framework linking genes, biochemistry, circuits, and clinical phenomenology, and 5) limited research funding. Identifying and discussing these challenges can help prioritize research efforts and resources, highlight the need for further investigation and funding, and inspire action towards addressing these challenges.

肌张力障碍指的是一组不同的运动障碍，其特征是肌肉不自主地持续收缩，导致重复性扭转动作和异常姿势。肌张力障碍的临床范围很广，可影响不同的身体部位，导致严重残疾和生活质量下降。尽管在了解肌张力障碍方面取得了重大进展，但肌张力障碍研究仍面临许多挑战。本微型综述旨在强调这一领域的基础研究和转化研究面临的主要挑战，包括：1）肌张力障碍的异质性；2）对其病理生理学的了解有限；3）使用动物模型的复杂性；4）缺乏将基因、生物化学、电路和临床现象学联系起来的框架；5）研究经费有限。识别和讨论这些挑战有助于确定研究工作和资源的优先次序，强调进一步调查和资助的必要性，并激励人们采取行动应对这些挑战。

引用次数: 0

Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias 肌张力障碍网络的功能和功能障碍：对后天性和孤立性肌张力障碍神经回路的探索

Dystonia

Pub Date : 2023-12-13 DOI: 10.3389/dyst.2023.11805

Jason S. Gill, Megan X. Nguyen, Mariam Hull, Meike E. van der Heijden, Ken Nguyen, Sruthi P. Thomas, R. Sillitoe

Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad “dystonia network” encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the “geste antagoniste” or “sensory trick” to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.

肌张力障碍是一种发病率很高的运动障碍疾病，可在人一生中的任何时候出现。越来越多的研究将这种疾病与包括小脑、丘脑、基底节和皮层在内的广泛 "肌张力障碍网络 "的功能障碍联系起来。然而，要精确定位该网络各解剖组成部分的功能障碍是如何导致不同病因引起的各种肌张力障碍表现的，仍然是一个难题。在这篇综述中，我们将讨论肌张力障碍非腱鞘炎病因中的功能网络发现。首先探讨了肌张力障碍的获得性病因以及病变位置如何导致网络功能的改变，并对脑瘫进行了研究，因为早期脑损伤可能导致肌张力障碍/运动障碍。然后，继续讨论获得性病因，评估有关病灶病变导致的肌张力障碍的文献，接着是孤立的病灶性肌张力障碍，包括特发性和任务依赖性两种。接着，研究肌张力障碍网络如何对治疗干预做出反应，从 "拮抗手势 "或 "感觉技巧 "到肉毒毒素和脑深部刺激，着眼于发现网络反应与有效治疗的相似之处。最后，文章还探讨了小鼠模型中的局灶性网络破坏如何帮助我们了解肌张力障碍所涉及的回路。总之，本文旨在对从大脑网络角度研究肌张力障碍的文献进行综述，并为将肌张力障碍视为网络功能紊乱的观点提供依据。

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引用次数: 0

Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia 肌张力障碍、震颤和共济失调啮齿动物模型的小脑功能障碍

Dystonia

Pub Date : 2023-12-08 DOI: 10.3389/dyst.2023.11515

Meike E. van der Heijden, R. Sillitoe

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.

肌张力障碍是一种运动障碍，其特征是肌肉不自主的共同收缩或过度收缩，导致异常的姿势和运动。这些症状是由全脑肌张力障碍网络的病理生理学引起的。越来越多的证据表明，小脑是这个网络的中心节点。例如，针对小脑的操作会引起小鼠的张力障碍症状，而小脑神经调节可以减轻这些症状。尽管许多研究结果为肌张力障碍的病理生理学提供了见解，但它们也提出了进一步的问题。也就是说，小脑病理生理是如何引起肌张力障碍、震颤和共济失调的各种运动异常的?在这里，我们描述了最近在啮齿动物中的工作，表明不同的小脑回路异常可以定义不同的疾病，我们讨论了决定小脑疾病行为表现的潜在机制。

引用次数: 0

A mini-review of the pathophysiology of task-specific tremor: insights from electrophysiological and neuroimaging findings 任务特异性震颤的病理生理学综述:来自电生理和神经影像学发现的见解

Dystonia

Pub Date : 2023-11-07 DOI: 10.3389/dyst.2023.11347

Yih-Chih Jacinta Kuo, Kai-Hsiang Stanley Chen

Task-specific tremor (TST) is a specific type of tremor that occurs when performing or attempting to perform a specific task, such as writing or playing a musical instrument. The clinical entity of TST remains heterogeneous. Some TSTs can only be induced by conducting a specific task, while others can be elicited when adopting a particular position simulating a task. The pathophysiology of TST is controversial. Whether TST is an isolated tremor syndrome, a spectrum of dystonic tremor syndrome (DTS), or essential tremor (ET) is not yet clear. Evidence from electrophysiological studies suggests that TST patients have normal reciprocal inhibition responses but abnormal motor cortical excitability, especially relating to the maladaptive long-interval intracortical inhibitory circuitry. The blink recovery study and eyeblink classical conditioning studies demonstrated possible hyperexcitability of the brainstem circuits and cerebellar dysfunction in patients with TST. Functional MRI studies have further shown that patients with TST have reduced functional connectivity in the cerebellum, similar to patients with DTS and ET. Due to variable methodologies and the sparsity of functional MRI studies in TST, it remains uncertain if patients with TST share the connectivity abnormalities between the cortical or subcortical areas that have been demonstrated in patients with DTS. Comprehensive electrophysiological and functional neuroimaging studies may help to elucidate the pathophysiology of TST.

任务特异性震颤(TST)是一种特定类型的震颤，发生在执行或试图执行特定任务时，如写作或演奏乐器。TST的临床实体仍然是异质性的。有些测试只能在执行特定任务时产生，而另一些则可以在采用特定位置模拟任务时产生。TST的病理生理学存在争议。TST是孤立性震颤综合征、肌张力障碍震颤综合征(DTS)还是特发性震颤(ET)尚不清楚。来自电生理研究的证据表明，TST患者具有正常的相互抑制反应，但运动皮质兴奋性异常，特别是与适应不良的长间隔皮质内抑制回路有关。眨眼恢复研究和眨眼经典条件反射研究表明，TST患者可能存在脑干回路的高兴奋性和小脑功能障碍。功能性MRI研究进一步表明，与DTS和ET患者类似，TST患者的小脑功能连通性降低。由于TST方法的变化和功能性MRI研究的稀缺性，尚不确定TST患者是否与DTS患者一样存在皮质或皮质下区域之间的连通性异常。全面的电生理和功能神经影像学研究可能有助于阐明TST的病理生理。

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引用次数: 0

Transcriptional regulatory network for neuron-glia interactions and its implication for DYT6 dystonia 神经元-胶质细胞相互作用的转录调控网络及其对DYT6肌张力障碍的影响

Dystonia

Pub Date : 2023-10-30 DOI: 10.3389/dyst.2023.11796

Dhananjay Yellajoshyula

Advances in sequencing technologies have identified novel genes associated with inherited forms of dystonia, providing valuable insights into its genetic basis and revealing diverse genetic pathways and mechanisms involved in its pathophysiology. Since identifying genetic variation in the transcription factor coding THAP1 gene linked to isolated dystonia, numerous investigations have employed transcriptomic studies in DYT-THAP1 models to uncover pathogenic molecular mechanisms underlying dystonia. This review examines key findings from transcriptomic studies conducted on in vivo and in vitro DYT-THAP1 models, which demonstrate that the THAP1-regulated transcriptome is diverse and cell-specific, yet it is bound and co-regulated by a common set of proteins. Prominent among its functions, THAP1 and its co-regulatory network target molecular pathways critical for generating myelinating oligodendrocytes that ensheath axons and generate white matter in the central nervous system. Several lines of investigation have demonstrated the importance of myelination and oligodendrogenesis in motor function during development and in adults, emphasizing the non-cell autonomous contributions of glial cells to neural circuits involved in motor function. Further research on the role of myelin abnormalities in motor deficits in DYT6 models will enhance our understanding of axon-glia interactions in dystonia pathophysiology and provide potential therapeutic interventions targeting these pathways.

测序技术的进步已经确定了与遗传性肌张力障碍相关的新基因，为其遗传基础提供了有价值的见解，并揭示了其病理生理中涉及的多种遗传途径和机制。由于发现了与孤立性肌张力障碍相关的转录因子编码THAP1基因的遗传变异，许多研究已经在DYT-THAP1模型中使用转录组学研究来揭示肌张力障碍的致病分子机制。本文回顾了在体内和体外DYT-THAP1模型上进行的转录组研究的主要发现，这些研究表明thap1调节的转录组是多样化的和细胞特异性的，但它是由一组共同的蛋白质结合和共同调节的。在其功能中，THAP1及其共调控网络针对的分子通路对髓鞘少突胶质细胞的生成至关重要，髓鞘少突胶质细胞包裹轴突，并在中枢神经系统中产生白质。一些研究已经证明了髓鞘形成和少突胶质形成在发育期间和成人运动功能中的重要性，强调了神经胶质细胞对参与运动功能的神经回路的非细胞自主贡献。进一步研究髓磷脂异常在DYT6模型运动缺陷中的作用，将增强我们对肌张力障碍病理生理中轴突-胶质细胞相互作用的理解，并提供针对这些通路的潜在治疗干预措施。

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引用次数: 0

Non-motor symptoms in dystonia: from diagnosis to treatment 肌张力障碍的非运动症状:从诊断到治疗

Dystonia

Pub Date : 2023-10-24 DOI: 10.3389/dyst.2023.11860

Kathryn J. Peall, Brian D. Berman, Norbert Bruggemann, Giovanni Defazio, Hortensia Gimeno, H. A. Jinnah, Joel S. Perlmutter, Sarah E. Pirio Richardson, Emmanuel Roze, Anette Schrag, Michele Tinazzi, Marie Vidailhet, Aparna Wagle Shukla, Yulia Worbe, Jan K. Teller, Davide Martino

The Dystonia Medical Research Foundation organized an expert virtual workshop in March 2023 to review the evidence on non-motor symptoms across the spectrum of dystonia, discuss existing assessment methods, need for their harmonisation and roadmap to achieve this, and evaluate potential treatment approaches. Albeit the most investigated non-motor domains, experts highlighted the need to identify the most accurate screening procedure for depression and anxiety, clarify their mechanistic origin and quantify their response to already available therapies. Future exploration of sleep disruption in dystonia should include determining the accuracy and feasibility of wearable devices, understanding the contribution of psychotropic medication to its occurrence, and defining the interaction between maladaptive plasticity and abnormal sleep patterns. Despite recent advances in the assessment of pain in dystonia, more research is needed to elucidate the relative importance of different mechanisms called into play to explain this impactful sensory feature and the most appropriate treatments. Amongst the different non-motor features investigated in dystonia, cognitive dysfunction and fatigue require an in-depth observation to evaluate their functional impact, their clinical profile and assessment methods and, in the case of cognition, whether impairment represents a prodrome of dementia. Finally, experts identified the development and field validation of a self-rated screening tool encompassing the full spectrum of non-motor symptoms as the most urgent step towards incorporating the management of these features into routine clinical practice.

肌张力障碍医学研究基金会于2023年3月组织了一次专家虚拟研讨会，以审查跨肌张力障碍谱系的非运动症状的证据，讨论现有的评估方法，需要它们的协调和实现这一目标的路线图，并评估潜在的治疗方法。尽管对非运动领域的研究最多，但专家们强调，需要确定最准确的抑郁和焦虑筛查程序，阐明其机制起源，并量化它们对现有疗法的反应。未来对肌张力障碍中睡眠中断的探索应包括确定可穿戴设备的准确性和可行性，了解精神药物对其发生的贡献，以及定义适应不良可塑性与异常睡眠模式之间的相互作用。尽管最近在肌张力障碍疼痛的评估方面取得了进展，但需要更多的研究来阐明不同机制的相对重要性，以解释这种有影响的感觉特征和最合适的治疗方法。在肌张力障碍研究的不同非运动特征中，认知功能障碍和疲劳需要深入观察，以评估其功能影响、临床特征和评估方法，以及在认知方面，损害是否代表痴呆的前驱症状。最后，专家们确定了一种包含全谱非运动症状的自评筛选工具的开发和现场验证，作为将这些特征管理纳入常规临床实践的最紧迫步骤。

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引用次数: 0

Functional imaging of deep brain stimulation in dystonia: a review 深部脑刺激治疗肌张力障碍的功能影像学研究进展

Dystonia

Pub Date : 2023-10-06 DOI: 10.3389/dyst.2023.11440

Ian O. Bledsoe, Melanie A. Morrison

Much remains to be learned about the mechanism of benefit of deep brain stimulation in movement disorders in general and dystonia specifically. A full accounting of the pathophysiology of dystonia additionally remains unclear. Given its ability to evaluate whole-brain network changes, functional neuroimaging is an important tool to advance understanding of the effects of deep brain stimulation, which in turn could offer insight into the pathophysiology of dystonia and suggest novel deep brain stimulation targets for the disorder. This review surveys the published literature of functional neuroimaging studies evaluating deep brain stimulation effects in dystonia, including PET, SPECT, and functional MRI studies. To date, study cohorts have been relatively small, though several general patterns emerge when studies are viewed collectively, including reduced functional activation patterns with stimulation turned on during motor tasks, particularly in frontal cortical regions. During rest with stimulation on, several studies showed areas of relatively decreased perfusion only in those participants who experienced clinical benefit from deep brain stimulation. Future research may benefit from larger cohorts with more homogeneous forms of dystonia, potentially enabled by multi-center initiatives. Additional benefits may result from more detailed longitudinal assessments and greater use of functional MRI, with study designs that take into account the technical limitations of this modality in the context of movement disorders and deep brain stimulation.

深部脑刺激对运动障碍和肌张力障碍的作用机制仍有待进一步研究。另外，肌张力障碍的病理生理机制还不清楚。鉴于其评估全脑网络变化的能力，功能神经成像是促进对脑深部刺激效应的理解的重要工具，这反过来可以为肌张力障碍的病理生理学提供见解，并为该疾病提供新的脑深部刺激靶点。本综述综述了已发表的功能性神经影像学研究，包括PET、SPECT和功能性MRI研究，评估深部脑刺激对肌张力障碍的影响。到目前为止，研究群体相对较小，尽管在整体研究中出现了几种普遍模式，包括在运动任务中，特别是在额叶皮质区域，由于刺激而减少的功能激活模式。在有刺激的休息期间，几项研究显示，只有那些从深部脑刺激中获益的参与者的脑灌注区域相对减少。未来的研究可能会受益于更多同质形式的肌张力障碍的更大的队列，潜在地通过多中心倡议实现。更多的益处可能来自更详细的纵向评估和更多地使用功能性MRI，研究设计考虑到这种模式在运动障碍和深部脑刺激背景下的技术局限性。

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引用次数: 0

The role of protein kinase R in dystonia 蛋白激酶R在肌张力障碍中的作用

Dystonia

Pub Date : 2023-09-22 DOI: 10.3389/dyst.2023.11718

Benjamin Dodd, Stephanie L. Moon

Dystonia is a progressive neurological motor disease with few treatment options and no cure. This review synthesizes the results of recent studies that implicate protein kinase R in mediating the molecular mechanisms of dystonia pathogenesis. Mutations in the PKR gene EIF2AK2 and the PKR activator protein PACT are associated with early-onset generalized dystonia. Protein kinase R (PKR) is important for neuronal function. Genetic depletion or inhibition of PKR is associated with increased long-term potentiation and memory, while also causing neuronal hyper-excitability and seizures in mouse models. PKR also senses double stranded RNA within cells and activates the integrated stress response (ISR). The ISR is a conserved signaling pathway that hinges on controlled translational suppression to remodel gene expression during stress. When PKR is activated through binding double stranded RNA or the PKR activator protein PACT, PKR dimerizes, autophosphorylates, and phosphorylates the translation initiation factor eIF2. Translation suppression by p-eIF2 causes stress granule formation and the upregulation of stress-induced genes. The ISR is thought to drive cellular resilience during acute stress. However, chronic ISR activation is associated with neurological diseases, traumatic brain injury, and aging. Neurodevelopmental and neurodegenerative diseases are associated with mutations in other integrated stress response genes, suggesting a critical role for ISR regulation in neuronal health. A growing body of work suggests the ISR is also dysfunctional in dystonia. Future research investigating the molecular mechanisms of the ISR in dystonia will likely reveal therapeutic targets and treatment strategies for this currently incurable disease.

肌张力障碍是一种进行性神经运动疾病，治疗方法很少，无法治愈。本文综述了近年来有关蛋白激酶R参与肌张力障碍发病机制的研究结果。PKR基因EIF2AK2和PKR激活蛋白PACT的突变与早发性全身性肌张力障碍有关。蛋白激酶R (PKR)在神经元功能中起重要作用。在小鼠模型中，基因缺失或PKR抑制与长时程增强和记忆增加有关，同时也引起神经元的超兴奋性和癫痫发作。PKR还能感知细胞内的双链RNA并激活综合应激反应(ISR)。ISR是一种保守的信号通路，在应激过程中依赖于有控制的翻译抑制来重塑基因表达。当PKR通过结合双链RNA或PKR激活蛋白PACT被激活时，PKR会二聚化、自磷酸化并磷酸化翻译起始因子eIF2。p-eIF2的翻译抑制导致应激颗粒的形成和应激诱导基因的上调。ISR被认为在急性压力下驱动细胞恢复力。然而，慢性ISR激活与神经系统疾病、创伤性脑损伤和衰老有关。神经发育和神经退行性疾病与其他综合应激反应基因的突变有关，表明ISR调控在神经元健康中起关键作用。越来越多的研究表明，ISR在肌张力障碍中也有功能障碍。未来研究ISR在肌张力障碍中的分子机制可能会揭示这种目前无法治愈的疾病的治疗靶点和治疗策略。

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引用次数: 0