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首页> 美国卫生研究院文献>Autophagy >Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA)
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Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA)

机译：帕金森氏病的突变LRRK2敲入小鼠模型中降解受损的寡聚SNCA /α-突触核蛋白的年龄依赖性积累：伴侣介导的自噬（CMA）的治疗激活作用。

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Parkinson disease (PD) is an age-related neurodegenerative disorder associated with misfolded SNCA/α-synuclein accumulation in brain. Impaired catabolism of SNCA potentiates formation of its toxic oligomers. (leucine-rich repeat kinase-2) mutations predispose to familial and sporadic PD. Mutant LRRK2 perturbs chaperone-mediated-autophagy (CMA) to degrade SNCA. We showed greater age-dependent accumulation of oligomeric SNCA in striatum and cortex of aged LRRK2 knockin (KI) mice, compared to age-matched wildtype (WT) by 53% and 31%, respectively. Lysosomal clustering and accumulation of CMA-specific LAMP2A and HSPA8/HSC70 proteins were observed in aged mutant striatum along with increased GAPDH (CMA substrate) by immunohistochemistry of dorsal striatum and flow cytometry of ventral midbrain cells. Using our new reporter protein clearance assay, mutant mouse embryonic fibroblasts (MEFs) expressing either SNCA or CMA recognition ‘KFERQ’-like motif conjugated with photoactivated-PAmCherry showed slower cellular clearance compared to WT by 28% and 34%, respectively. However, such difference was not observed after the ‘KFERQ’-motif was mutated. LRRK2 mutant MEFs exhibited lower lysosomal degradation than WT indicating lysosomal dysfunction. LAMP2A-knockdown reduced total lysosomal activity and clearance of ‘KFERQ’-substrate in WT but not in mutant MEFs, indicating impaired CMA in the latter. A CMA-specific activator, AR7, induced neuronal LAMP2A transcription and lysosomal activity in MEFs. AR7 also attenuated the progressive accumulation of both intracellular and extracellular SNCA oligomers in prolonged cultures of mutant cortical neurons (DIV21), indicating that oligomer accumulation can be suppressed by CMA activation. Activation of autophagic pathways to reduce aged-related accumulation of pathogenic SNCA oligomers is a viable disease-modifying therapeutic strategy for PD.
机译：帕金森病（PD）是与年龄相关的神经退行性疾病，与大脑中SNCA /α-突触核蛋白积聚不正确有关。 SNCA的分解代谢受损会增强其有毒寡聚物的形成。 （富含亮氨酸的重复激酶2）突变易患家族性和散发性PD。突变的LRRK2扰动伴侣介导的自噬（CMA）降解SNCA。我们显示老年LRRK2敲入（KI）小鼠的纹状体和皮质中寡聚SNCA的年龄依赖性更大的积累，相比于年龄匹配的野生型（WT）分别低53％和31％。通过背侧纹状体的免疫组织化学和腹侧中脑细胞的流式细胞术，在衰老的突变体纹状体中观察到了CMA特异性LAMP2A和HSPA8 / HSC70蛋白的溶酶体聚簇和积累，同时GAPDH（CMA底物）增加。使用我们的新报告基因蛋白质清除试验，表达SNCA或CMA识别的“ KFERQ”样基序与光活化PAmCherry结合的突变小鼠胚胎成纤维细胞（MEF）与野生型相比，细胞清除率分别降低了28％和34％。但是，在对“ KFERQ”基序进行突变后，未观察到这种差异。 LRRK2突变MEF表现出比WT低的溶酶体降解，表明溶酶体功能障碍。 LAMP2A敲低降低了野生型中的总溶酶体活性和“ KFERQ”底物的清除，但没有降低突变型MEF，表明后者的CMA受损。 CMA特异性激活剂AR7诱导MEF中的神经元LAMP2A转录和溶酶体活性。在突变皮质神经元（DIV21）的长时间培养中，AR7还减弱了细胞内和细胞外SNCA寡聚体的逐步积累，表明CMA激活可抑制寡聚体的积累。自噬途径的激活以减少与年龄相关的病原性SNCA低聚物的积累是PD可行的疾病改良治疗策略。

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