Targeting nigral tyrosine hydroxylase to improve locomotion in aging

描述（由申请人提供）：主动活动的能力对于进行日常生活活动是必不可少的。从退休年龄开始，运动迟缓，即运动活动的显著减少，对这项能力的损害构成了主要风险，65岁和85岁的老年人中分别有15%和50%的人致残。即将到来的退休年龄人口的爆炸和他们预期的寿命增长使得现在必须确定与年龄相关的运动迟缓的神经生物学基础和可以在中年时开始的生活方式策略，以减少其风险。运动迟缓是帕金森病（PD）的主要症状，当纹状体多巴胺（DA）丢失超过70%时出现。在这方面，与年龄相关的运动迟缓与PD非常不同，纹状体DA损失差异很大，但从未超过70%。而在黑质（SN）中，PD和衰老对DA损失的减少程度相似。黑质多巴胺的释放是公认的，但事实是黑质多巴胺会影响

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 ?-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 ?-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.