Molecular mechanisms of pathological protein propagation and its regulation

进行性神经变性伴异常蛋白堆积是包括路易体病(LBD)和ALS/FTLD在内的许多神经退行性疾病的典型神经病理特征。我们发现，注射重组α-突触核蛋白(AS)纤维有效地诱导了野生型小鼠AS病理过度磷酸化。生化分析表明，内源性AS在接种后3个月开始蓄积。此外，注射LBD患者的Sarkosyl不溶性AS引起的与病理相似的结果，表明AS原纤维显示出普恩病毒样的感染性。我们还证明了不可溶的TDP-43具有类似普里恩的性质。这些结果表明，病理蛋白可能在具有蛋白质病理学的神经退行性疾病的进展中发挥作用。这些细胞和小鼠模型对于阐明进展机制和评估疾病修饰疗法应该是有用的。

Progressive neurodegeneration with accumulation of abnormal proteins is the defining neuropathological feature of many neurodegenerative diseases, including Lewy body disease (LBD) and ALS/FTLD. We revealed that injections of recombinant alpha-synuclein (aS) fibrils efficiently induced hyperphosphorylated aS pathology in wild-type mice. Biochemical analyses demonstrated that endogenous mouse aS started to accumulate 3 months after inoculation. Furthermore, injections of Sarkosyl-insoluble aS from LBD patients induced similar aS pathology, indicating that aS fibrils show prion-like infectivity. We also demonstrated that insoluble TDP-43 has prion-like properties. These results indicate that pathological proteins may play a role in the progression of neurodegenerative diseases with protein pathologies. These cellular and mouse models should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.