Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Wagistrasse 12, Schlieren, 8952, Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
Neurotox Res. 2018 Apr;33(3):560-568. doi: 10.1007/s12640-017-9843-5. Epub 2017 Dec 7.
Parkinson's disease is the most common neurodegenerative disorder after Alzheimer's disease, with the majority of cases being sporadic or "idiopathic". The aetiology of the sporadic form is still unknown, but there is a broad consensus that Parkinson's disease involves multiple pathways. In previous human post-mortem studies investigating substantia nigra of parkinsonian subjects, gene expression alterations in various metabolic pathways including protein folding, trafficking, aggregation, ubiquitination and oxidative stress were found. These studies revealed transcriptomic dysregulation of various genes, amongst others Skp1A and PSMC4 (part of ubiquitin-proteasome system), HSC70 (belonging to the chaperone family) and ALDH1A1 (an enzyme involved in the catabolism of dopamine). To investigate whether these alterations are manifested at the protein level, we performed immunohistochemical analysis in the substantia nigra of Parkinson's disease and compared them to Alzheimer's disease and non-neurological post-mortem controls. We were able to confirm cell-specific reductions in the protein content of ALHD1A1 and Skp1A in the dopaminergic neurons of the substantia nigra of Parkinsonian patients compared to Alzheimer's and control subjects. Furthermore, we observed particular distribution for HSC70 and PSMC4 in the cytoplasm and accumulation within Lewy body in the dopaminergic neurons of the substantia nigra in Parkinson patients. These findings, together with previous evidence, suggest a malfunction of the ubiquitin-proteasome and possible autophagy systems as major players in protein misfolding and aggregation in Parkinson's disease. Nevertheless, this needs further proof, possibly with trajectory time line.
帕金森病是继阿尔茨海默病之后最常见的神经退行性疾病，大多数病例为散发性或“特发性”。散发性疾病的病因仍不清楚，但广泛认为帕金森病涉及多个途径。在以前对帕金森病患者黑质进行的人类死后研究中，发现了包括蛋白质折叠、运输、聚集、泛素化和氧化应激在内的各种代谢途径中的基因表达改变。这些研究揭示了 Skp1A 和 PSMC4（泛素-蛋白酶体系统的一部分）、HSC70（属于伴侣家族）和 ALDH1A1（参与多巴胺分解代谢的酶）等各种基因的转录组失调。为了研究这些改变是否在蛋白质水平上表现出来，我们在帕金森病患者的黑质中进行了免疫组织化学分析，并将其与阿尔茨海默病和非神经死后对照组进行了比较。我们能够证实与阿尔茨海默病和对照组相比，帕金森病患者黑质中的多巴胺能神经元中 ALDH1A1 和 Skp1A 的蛋白含量存在特定的细胞减少。此外，我们观察到 HSC70 和 PSMC4 在帕金森病患者黑质中的多巴胺能神经元中的细胞质中存在特定分布，并在Lewy 体中积累。这些发现与之前的证据一起表明，泛素-蛋白酶体和可能的自噬系统的功能障碍是帕金森病中蛋白质错误折叠和聚集的主要因素。然而，这需要进一步的证据，可能需要进行轨迹时间线分析。
