Targeting nigral tyrosine hydroxylase to improve locomotion in aging

描述（由申请人提供）：启动运动的能力对于进行日常生活活动至关重要。从退休年龄开始，运动迟缓，即运动活动的显著减少，对这种能力造成了损害的主要风险，使15%的65岁以上的人和50%的85岁以上的人致残。即将到来的爆炸在退休年龄的人口和他们的预期寿命增加，现在必须确定与年龄相关的运动迟缓和生活方式的策略，可以在中年开始，以减少其风险的神经生物学基础。运动迟缓是帕金森病（PD）的主要症状，当纹状体多巴胺（DA）损失超过70%时出现。在这方面，帕金森病相关的运动迟缓与PD非常不同，因为纹状体DA损失变化很大，但从未超过70%。然而，在黑质（SN），PD和衰老减少DA损失的程度相似。黑质多巴胺的释放是公认的，但事实上，黑质DA可以影响 行为被忽视了。事实上，黑质DA信号的干扰阻碍了运动活动。我们最近报道了一个显着的相关性黑质，但纹状体DA与自发活动。因此，黑质DA可用于改善与年龄相关的运动迟缓。酪氨酸羟化酶（TH）是DA生物合成中的限速酶，受磷酸化调节，并受生长因子GDNF的影响。值得注意的是，GDNF增加自发活动，黑质DA组织含量，和黑质TH磷酸化ser 31。该磷酸化位点对DA组织含量具有显著影响。衰老降低了黑质中GDNF受体GFR α-1、TH蛋白、ser 31 TH磷酸化和DA的表达。我们建议这些赤字有助于年龄相关的运动迟缓。策略显示，以减轻运动迟缓，运动和热量限制（这两个也增加GDNF的表达），提出防止这些衰老相关的分子缺陷的SN。我们将通过以下方式确定黑质DA的年龄相关性降低是否有助于年龄相关性运动迟缓：1）实验性抑制年轻大鼠中的TH活性以降低DA并量化其对运动活性的影响，以及2）用黑质L-DOPA输注绕过老年大鼠中的TH活性缺陷以量化对运动迟缓的影响。我们还将确定在12至18个月大的婴儿中，（黑质TH和DA降低时期）将增加黑质GFR α-1、TH蛋白和ser 31 TH磷酸化水平，这个合作项目将确定改善老年人运动能力的治疗策略，并确定减轻运动迟缓的生活方式策略的分子影响在中年时开始。

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.