Targeting nigral tyrosine hydroxylase to improve locomotion in aging

描述(申请人提供)：启动运动的能力是进行日常生活活动所必需的。从退休年龄开始，运动能力显著下降的运动迟缓是这种能力受损的主要风险，在65岁和85岁的人中，分别有15%和50%的人致残。退休老年人口即将激增，预计他们的寿命会增加，这使得现在必须确定与年龄相关的运动迟缓和生活方式战略的神经生物学基础，这些战略可以在中年时启动，以降低其风险。运动迟缓是帕金森氏病(PD)的一个主要症状，当纹状体多巴胺(DA)丢失超过70%时出现。年龄相关性运动迟缓在这方面与帕金森病非常不同，因为纹状体DA的丢失差异很大，但永远不会超过70%。然而，在黑质(SN)，PD和衰老减少DA丢失的程度相似。黑质多巴胺的释放已得到很好的证实，但黑质DA可以影响 行为一直被相当忽视。事实上，对黑质DA信号的干扰阻碍了运动活动。我们最近报道黑质DA与运动活动显著相关，但纹状体DA与运动活动无关。因此，黑质DA可作为改善年龄相关性运动迟缓的靶点。酪氨酸羟化酶(TH)是DA生物合成的限速酶，受磷酸化调控，受生长因子GDNF的影响。值得注意的是，GDNF增加了运动活性、黑质DA组织含量和黑质TH在SER31的磷酸化。该磷酸化位点对DA组织含量有显著影响。增龄使黑质中胶质细胞源性神经营养因子受体α-1、TH蛋白、血清31TH磷酸化和DA的表达减少。我们认为这些缺陷与年龄相关的运动迟缓有关。研究人员提出了缓解运动迟缓、运动和热量限制(两者都会增加GDNF表达)的策略，以防止SN中这些与衰老相关的分子缺陷。我们将通过1)实验抑制幼年大鼠TH活性以降低DA并量化其对运动活动的影响，以及2)通过黑质L多巴输注绕过老年大鼠TH活性缺陷以量化其对运动迟缓的影响，以确定黑质DA的增龄性减少是否与老年性运动迟缓有关。我们还将确定在12-18个月龄(黑质TH和DA减少的时期)进行运动或热量限制的干预是否会增加黑质GFRα-1、TH蛋白和血清31 TH磷酸化以及DA的水平。这一合作项目将确定改善老年人运动能力的治疗策略，并确定在中年启动时缓解运动迟缓的生活方式策略的分子影响。

DESCRIPTION (provided by applicant): The ability to initiate movement is essential for performing activities of daily living. Beginning at retirement age, bradykinesia, a significant decrease in locomotor activity, poses a major risk of impairment to this ability, disabling 15% of those reaching age 65 and 50% of those reaching age 85. The impending explosion in the retirement-aged population and their projected increase in longevity make it now imperative to determine the neurobiological basis of age-related bradykinesia and lifestyle strategies that can be initiated at middle-age to reduce its risk. Bradykinesia is a cardinal symptom of Parkinson's disease (PD) that appears when striatal dopamine (DA) loss exceeds 70%. Age-related bradykinesia is very much unlike PD in this regard, as striatal DA loss varies considerably but never exceeds 70%. However in the substantia nigra (SN), PD and aging decrease DA loss to a similar extent. Nigral dopamine release is well established, but the fact that nigral DA can affect behavior has been rather neglected. Indeed, interference with nigral DA signaling impedes locomotor activity. We have recently reported a significant correlation of nigral, but not striatal DA with locomotor activity. Nigral DA could therefore be targeted to improve age-related bradykinesia. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in DA biosynthesis, is regulated by phosphorylation, and is influenced by the growth factor GDNF. Notably, GDNF increases locomotor activity, nigral DA tissue content, and nigral TH phosphorylation at ser31. This phosphorylation site has significant influence on DA tissue content. Aging decreases the expression of the GDNF receptor GFR α-1, TH protein, ser31 TH phosphorylation, and DA in the SN. We propose these deficits contribute to age-related bradykinesia. Strategies shown to mitigate bradykinesia, exercise and caloric restriction (both of which also increase GDNF expression), are proposed to prevent these aging-related molecular deficiencies in SN. We will determine if age-related decreases in nigral DA contribute to age-related bradykinesia by 1) experimentally inhibiting TH activity in young rats to decrease DA and quantifying its impact on locomotor activity, and 2) bypassing deficient TH activity in aged rats with nigral L-DOPA infusion to quantify the impact on bradykinesia. We will also determine if the interventions of exercise or caloric restriction between 12 and 18 months of age (the period when nigral TH and DA decrease) will increase nigral levels of GFR α-1, TH protein and ser31 TH phosphorylation, and DA. This collaborative project will identify therapeutic strategies to improve locomotion in the elderly and determine the molecular impact of lifestyle strategies shown to alleviate bradykinesia when initiated during middle-age.