Exercise and pharmacological LRRK2 inhibition for preventing PD

在美国，轻度创伤性脑损伤（mTBI）导致帕金森病（PD）的风险增加56%。 老兵PD在临床上表现为静止性震颤、平衡问题、步态不稳和运动缺陷。 PD的组织学标志是α-突触核蛋白（α-syn）病理通过相互连接的大脑扩散 区域，和选择性损失的多巴胺能神经元在黑质pars延髓（SNpc）。没有 治愈PD和治疗只能治标不治本。随着OEF/OIF退伍军人进入中年，当诊断 随着PD的发病率越来越高，重要的是要确定增加潜在风险的因素和事件。 发展中的PD，更重要的是，减缓其进展的潜在缓解因素。运动已被 显示可防止与年龄相关的大脑退化，并与更好的白色纤维完整性相关 从而改善轻度认知障碍患者的执行功能。环境富集 在动物和康复，包括物理治疗的病人，已被证明显着改善 减少TBI患者的住院时间。然而，运动在预防 mTBI康复期间的PD未知。全基因组关联研究将突变与 富含亮氨酸重复激酶-2导致病理学上无法与特发性PD区分的迟发性PD。这些 研究结果表明，LRRK 2可能也在PD的非遗传原因中发挥作用。最近的体外和体内研究 研究表明，抑制WT-LRRK 2或功能获得性LRRK 2突变体中的激酶活性， 在神经炎症和PD模型中的神经保护。到目前为止，所有针对 预防或阻止PD进展在人类临床试验中失败，这可能是由于临床前 这些研究主要依赖于不完整的PD动物模型。尽管尽了最大努力，但使用这些不完整的 PD模型（例如，在PD中受影响的脑区中神经毒素诱导的病变，而不伴随α-syn 病理学）也未能在mTBI和PD之间产生真正的生物学联系。这种不明确性是 这可能是为什么目前没有有效的康复方法或治疗来阻止或预防PD。注射 致淀粉样蛋白生成的预形成α-syn纤维（PFF）进入啮齿动物的SNpc，导致人类- 像α-syn病理通过相互连接的大脑区域，进行性和选择性多巴胺能 神经变性与PD相关的行为缺陷。使用这个更完整的迟发性PD模型，我们 计划确定mTBI和PD之间的联系，并测试可能预防PD的潜在治疗方法。 我们的总体假设是，重复性mTBI（r-mTBI）促进了脆弱个体（即， 未检测到PD的患者），但运动结合新的药物治疗可以延缓PD的进展。 PD，即使在脆弱的人。我们将在PFF诱导的PD模型中检验我们的假设， 运动沿着LRRK 2的药理学抑制可以预防PD。使用高度特异性LRRK 2抑制剂 进入人体试验治疗诊断的PD，这是至关重要的，以确定是否与运动，这类 可以预防高危人群中的PD。除了支持科学目标，这项事业 发展奖将为Delic博士提供不同模型的脑损伤和行为训练， 以及VA新泽西卫生保健系统的神经生理学结果测量。本次培训将 使Delic博士能够成功地将这种和未来的治疗方法应用于临床。

Mild Traumatic Brain Injury (mTBI) results in a 56% higher risk of developing Parkinson’s disease (PD) in U.S. Veterans. PD presents clinically with resting tremors, balance problems, gait instability, and locomotor deficits. Histological hallmarks of PD are spread of alpha synuclein (α-syn) pathology through interconnected brain regions, and selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). There is no cure for PD and treatments are only palliative. With OEF/OIF Veterans entering middle-age, when the diagnosis of PD becomes more prevalent, it is important to identify factors and events that increase the risk of potentially developing PD and, more importantly, potential mitigating factors that slow its progression. Exercise has been shown to prevent age-related brain deterioration and is associated with better white matter fiber integrity resulting in improved executive function in patients with mild cognitive impairment. Environmental enrichment in animals and rehabilitation including physiotherapy in patients, have been shown to significantly improve recovery and decrease hospital stay in patients with TBI. However, the effectiveness of exercise at preventing PD during rehabilitation from mTBI is unknown. Genome wide association studies have linked mutations in Leucine Rich Repeat Kinase-2 to late onset PD that is pathologically indistinguishable from idiopathic PD. These findings suggest that LRRK2 likely also plays a role in non-genetic causes of PD. Recent in vitro and in vivo studies show that inhibition of kinase activity in WT-LRRK2 or gain-of-function LRRK2 mutants, confers robust neuroprotection in models of neuroinflammation and PD. To date, all pharmacological treatments aimed at preventing or stopping PD progression have failed in human clinical trials and this may be due to preclinical studies that relied primarily on incomplete PD animal models. In spite of best efforts, use of these incomplete PD models, (e.g. neurotoxin induced lesions in brain areas affected in PD without accompanying α-syn pathology) has also failed to produce a bonafide biological link between mTBI and PD. This lack of clarity is likely why no effective rehabilitation methods or treatments to stop or prevent PD currently exist. Injection of amyloidogenic pre-formed α-syn fibrils (PFF) into the SNpc of rodents causes formation and spread of human- like α-syn pathology through the interconnected brain regions, progressive and selective dopaminergic neurodegeneration with PD related behavioral deficits. Using this more complete model of late onset PD, we plan to determine the connection between mTBI and PD and to test potential treatments that may prevent PD. Our overall hypothesis is that repetitive mTBI (r-mTBI) promotes PD pathology in vulnerable individuals (i.e. those with undetected PD), but exercise combined with new pharmacotherapies can delay the progression of PD, even in vulnerable individuals. We will test our hypothesis in the PFF induced model of PD and test if exercise along with pharmacological inhibition of LRRK2 can prevent PD. With highly specific LRRK2 inhibitors entering human trials for treating diagnosed PD, it is essential to determine if together with exercise, this class of drugs can prevent PD in at risk populations. In addition to supporting the scientific objectives, this career development award will provide Dr. Delic with training in different models of brain injury and behavioral as well as neurophysiological outcome measures at the VA New Jersey Health Care System. This training will enable Dr. Delic to successfully translate this and future treatments to the clinic.