Tau accumulation in the pedunculopontine tegmentum as an early node in Progressive Supranuclear Palsy pathogenesis

总结 进行性核上性麻痹（PSP）是一种多脑区tau蛋白聚集的衰弱性疾病 区域和严重的精神和运动缺陷。PSP常被误诊为帕金森病（50%） 也没有药物可以帮助PSP患者。PSP患者的预期寿命只有6-8年， 这表明当症状变得明显时，神经退行性疾病已经严重了。 因此，需要i）提高诊断的准确性，ii）找到生物标志物或行为缺陷， 在症状出现之前，以及iii）找到治疗方法。为了实现这些目标，我们需要了解1）从 疾病起源于大脑的何处，2）哪些神经通路在退化时产生哪些神经通路， 症状，和3）发病机制的地形进展。根据初步数据，我们 我们提出，在脑内，Tau蛋白在脑桥脚被盖（PPT）胆碱能神经元中的积累， 后脑将在PSP中受影响的脑区域中产生tau聚集体，从无病状态进展到 PSP样终末期，并产生PSP样行为缺陷（例如，额叶执行障碍综合征和运动障碍）。 赤字）。 为了在大鼠中产生PSP样病理，我们使用基因工程病毒选择性地过表达 在胆碱能PPT神经元的PSP（1 N4 R）中占优势的tau蛋白的同种型。术后5个月， 感染后，该模型与PSP一致：i）胆碱能神经元丢失，ii）黑质丢失， 多巴胺能神经元，iii）过度磷酸化tau阳性神经元的数量增加，iv）声惊吓 反射缺陷，和v）运动缺陷。将具有tau蛋白过表达的动物与那些 每隔5个月有一种良性蛋白质的过度表达，直到老年。我们将全面 死后组织化学分析，磁共振成像（MRI），REM睡眠记录， 行为测试（如认知和运动），以确定病理是否进展到一个条件 与后期PSP一致 一旦确定tau蛋白在胆碱能PPT神经元中的积累足以产生迟发性 阶段PSP样病理和行为缺陷，未来的工作将包括：1）确定策略， 改善病理学和疾病进展，2）发现疾病发作的早期标志物，和3） 分子机制研究（例如特定靶点的敲除）。

Summary Progressive Supranuclear Palsy (PSP) is a debilitating disease with aggregates of tau protein in multiple brain areas and severe mental and motor deficits. PSP is often misdiagnosed as Parkinson's Disease (rate of 50%) and there are no drugs that help PSP sufferers. Those with PSP have a life expectancy of only 6-8 years, suggestive that the neurodegeneration is already far advanced when symptomology becomes evident. Therefore, there is a need to i) increase the accuracy of diagnosis, ii) find biomarkers or behavioral deficits that predate the symptoms, and iii) find therapeutics. To facilitate these goals, we need to understand 1) from where within the brain does the disease originate, 2) which neural pathways when degenerated produce which symptoms, and 3) the topographical progression of pathogenesis. Based on strong preliminary data, we propose that the accumulation of tau protein in cholinergic pedunculopontine tegmentum (PPT) neurons in the hindbrain will produce tau aggregates in brain regions impacted in PSP, progress from a disease-free state to a PSP-like end stage, and produce PSP-like behavioral deficits (e.g. dysexecutive frontal syndrome and motor deficits). To produce PSP-like pathology in rats we use a genetically engineered virus to selectively over-express the isoform of the tau protein that predominates in PSP (1N4R) in cholinergic PPT neurons. At 5 months post- infection, the model is consistent with PSP: i) a loss of cholinergic neurons, ii) loss of substantia nigra dopaminergic neurons, iii) increased number of hyperphosphorylated tau-positive neurons, iv) acoustic startle reflex deficit, and v) motor deficits. Animals with tau protein over-expression will be compared to those that have the over-expression of a benign protein at 5 month intervals until old age. We will complete extensive postmortem histochemical analysis, Magnetic Resonance Imaging (MRI), REM sleep recordings, and behavioral testing (e.g. cognitive & motor) to establish whether the pathology progresses to a condition consistent with late-stage PSP. Once it is established that accumulation of tau in the cholinergic PPT neurons is sufficient to produce late stage PSP-like pathology and behavior deficits, future work would include: 1) identifying strategies that ameliorate symptomology and disease progression, 2) the discovery of early markers of disease onset, and 3) molecular mechanistic studies (e.g. knockdown of specific targets).