Mechanisms of motor superperformance

运动超性能的机制

基本信息

  • 批准号:
    10701427
  • 负责人:
  • 金额:
    $ 53.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-21 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

MECHANISMS OF MOTOR SUPERPERFORMANCE: ABSTRACT Clinical experience and world population-level data indicate that most neurological disability stems from motor dysfunction. Yet, spontaneous superperformer mutations occur in a variety of species including man, illustrating that the intrinsic motor capacity of the organism can be augmented. We set out to identify similar mutations by rotarod screening of 33,806 laboratory mice harboring chemically induced random mutations with the goal of mechanistically explaining and, eventually, pharmacologically enabling the phenomenon of motor superperformance. In this context, we have discovered that a mutation in an unsuspected gene, Rif1 (Replication Timing Regulatory Factor 1), confers supernormal motor ability. Using clustered regularly interspaced short palindromic repeats (CRISPR) Rif1-mutant mice, we have determined that: 1) mutant superperformance is a selective phenotype, with distinct changes in motor features quantifiable by our novel analysis method, but no other effects upon rigorous behavioral testing, and 2) the mutation also leads to accelerated motor recovery from stroke. The superperformance mechanism, however, is unknown: although Rif1 participates in DNA repair and in transcriptional regulation via G4 folded DNA structural stabilization, little is known about its function in the nervous system. There is precedent that DNA repair may be associated to synaptic transmission strength, while DNA G4 regulation could enhance the transcription of genes active in the motor system. We have refined this hypothetical framework by identifying several consequences of the Rif1 mutation: a) Increased cerebellar Purkinje cell firing regularity and local field potential changes in the non- moving mouse, which can influence movement precision, with change of these neurophysiological parameters upon locomotion on a treadmill; b) Increased resistance to DNA-damaging radiation; c) Increased resistance to G4 stabilization; d) Overexpression of a fraction of the cerebellar (but not forebrain or spinal cord) synaptic transcriptome including potential Rif1 mutation mediators such as Kcnma1, Kif5c and Nab2; e) These transcripts may be relevant to the phenotype because we show that loss of function mutations in them degrade motor performance, whereas f) Cerebellar injection of adenovirus-containing Nab2 induces superperformance. This proposal unifies this body of work by postulating that the Rif1 mutation modifies DNA repair and/or G4 DNA folding resulting in upregulation of synaptic transcripts, with either one or both mechanisms augmenting the precision of cerebellar synapse activity relevant to movement control. To this effect, we will conduct neurophysiological studies, determine the transcriptome in single cells, alter Kcnma1, Kif5c and Nab2 expression, and investigate DNA repair and DNA G4 regulation to test which of these mechanisms enable the superperformance phenotype. Our goal is to initiate and steer the mechanistic investigation (by us or any others) of Rif1 in the brain for ultimate therapeutic gain if appropriate.
电动机超性能的机理 临床经验和世界人口水平的数据表明,大多数神经系统残疾源于运动 功能障碍然而,自发的超级突变发生在包括人类在内的各种物种中, 说明生物体的内在运动能力可以增强。我们开始寻找类似的 通过旋转棒筛选33,806只携带化学诱导随机突变的实验室小鼠, 目的是机械地解释,并最终使电机现象, 超性能在这种情况下,我们发现一个未被怀疑的基因Rif 1的突变, (复制定时调节因子1),赋予超常的运动能力。定期使用群集 间隔短回文重复序列(CRISPR)Rif 1突变小鼠,我们已经确定:1)突变 超级表现是一种选择性表型,运动特征的明显变化可通过我们的新方法量化。 分析方法,但对严格的行为测试没有其他影响,2)突变还导致 加速中风后的运动恢复然而,超性能机制尚不清楚:尽管 Rif 1通过G4折叠DNA结构稳定参与DNA修复和转录调控, 已知它在神经系统中的功能。有先例表明,DNA修复可能与 突触传递强度,而DNA G4调节可以增强在突触传递中活跃的基因的转录。 运动系统我们通过确定Rif 1的几个后果来完善这个假设框架 突变:a)增加小脑浦肯野细胞放电规律性和局部场电位变化的非- 这些神经生理参数的变化会影响运动的精度 在跑步机上运动时; B)对DNA损伤性辐射的抗性增加; c)对DNA损伤性辐射的抗性增加。 G4稳定; d)小脑(但不是前脑或脊髓)突触的一部分的过表达, 转录组,包括潜在的Rif 1突变介导物,如Kcnma 1、Kif 5c和Nab 2; 转录本可能与表型相关,因为我们发现它们中的功能缺失突变会降低 运动表现,而f)小脑注射含有Nab 2的腺病毒诱导超表现。 该提案通过假设Rif 1突变修饰DNA修复和/或G4 DNA折叠导致突触转录物上调,其中一种或两种机制增强 与运动控制相关的小脑突触活动的精确性。为此,我们将 神经生理学研究,确定单细胞中的转录组,改变Kcnma 1,Kif 5c和Nab 2 表达,并研究DNA修复和DNA G4调节,以测试这些机制中的哪一个能够使 超级表现型我们的目标是启动和引导机械调查(由我们或任何 其他人)的Rif 1在大脑中的最终治疗收益,如果合适的话。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genetic influences on motor learning and superperformance mutants revealed by random mutational survey of mouse locomotion.
通过对小鼠运动的随机突变调查揭示了遗传对运动学习和超性能突变体的影响。
  • DOI:
    10.1101/2023.06.28.546756
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jakkamsetti,Vikram;Ma,Qian;Angulo,Gustavo;Scudder,William;Beutler,Bruce;Pascual,JuanM
  • 通讯作者:
    Pascual,JuanM
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Juan M. Pascual其他文献

Exosomes in disease: Epigenetic signals from the nervous system to the rest of the organism
  • DOI:
    10.1016/j.neulet.2019.134293
  • 发表时间:
    2019-08-24
  • 期刊:
  • 影响因子:
  • 作者:
    Juan M. Pascual;Denis Noble
  • 通讯作者:
    Denis Noble
Charcot-Marie-Tooth Disease
  • DOI:
    10.1017/9781107323704.088
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Juan M. Pascual
  • 通讯作者:
    Juan M. Pascual
PLA2G6 Gene
PLA2G6基因
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Juan M. Pascual
  • 通讯作者:
    Juan M. Pascual

Juan M. Pascual的其他文献

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{{ truncateString('Juan M. Pascual', 18)}}的其他基金

Dietary treatment of Glut1 deficiency (G1D) - Revision - 1
Glut1 缺乏症 (G1D) 的饮食治疗 - 修订版 - 1
  • 批准号:
    10447556
  • 财政年份:
    2021
  • 资助金额:
    $ 53.97万
  • 项目类别:
Pyruvate dehydrogenase encephalopathy: mechanisms and therapy
丙酮酸脱氢酶脑病:机制和治疗
  • 批准号:
    10225409
  • 财政年份:
    2017
  • 资助金额:
    $ 53.97万
  • 项目类别:
Pyruvate dehydrogenase encephalopathy: mechanisms and therapy
丙酮酸脱氢酶脑病:机制和治疗
  • 批准号:
    10000180
  • 财政年份:
    2017
  • 资助金额:
    $ 53.97万
  • 项目类别:
Dietary treatment of Glucose Transporter Type 1 Deficiency (G1D)
1 型葡萄糖转运蛋白缺乏症 (G1D) 的饮食治疗
  • 批准号:
    9755514
  • 财政年份:
    2016
  • 资助金额:
    $ 53.97万
  • 项目类别:
Dietary treatment of Glucose Transporter Type 1 Deficiency (G1D)
1 型葡萄糖转运蛋白缺乏症 (G1D) 的饮食治疗
  • 批准号:
    9538850
  • 财政年份:
    2016
  • 资助金额:
    $ 53.97万
  • 项目类别:
Modulation of neural function in energy failure
能量衰竭时神经功能的调节
  • 批准号:
    8373828
  • 财政年份:
    2012
  • 资助金额:
    $ 53.97万
  • 项目类别:
Modulation of neural function in energy failure
能量衰竭时神经功能的调节
  • 批准号:
    9099978
  • 财政年份:
    2012
  • 资助金额:
    $ 53.97万
  • 项目类别:
Modulation of neural function in energy failure
能量衰竭时神经功能的调节
  • 批准号:
    8472552
  • 财政年份:
    2012
  • 资助金额:
    $ 53.97万
  • 项目类别:
Modulation of neural function in energy failure
能量衰竭时神经功能的调节
  • 批准号:
    8693035
  • 财政年份:
    2012
  • 资助金额:
    $ 53.97万
  • 项目类别:
Modulation of neural function in energy failure
能量衰竭时神经功能的调节
  • 批准号:
    8882564
  • 财政年份:
    2012
  • 资助金额:
    $ 53.97万
  • 项目类别:

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