Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Department of Psychiatry, South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South Africa.
Department of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa.
Neurobiol Aging. 2021 Apr;100:91-105. doi: 10.1016/j.neurobiolaging.2020.12.013. Epub 2020 Dec 24.
Development of efficacious treatments for Parkinson's disease (PD) demands an improved understanding of mechanisms underlying neurodegeneration. Two cellular death pathways postulated to play key roles in PD are autophagy and apoptosis. Molecular overlap between these pathways was investigated through identifying studies that used therapeutic compounds to alter expression of specific molecular components of the pathways. Bcl-2 was identified as an important protein with the ability to suppress autophagy and apoptosis through inhibiting Beclin-1 and Bax, respectively. Involvement of c-Jun N-terminal kinases (JNK) and p38, was evident in the activation of apoptosis through increasing the Bax/Bcl-2 ratio. JNK-mediated phosphorylation also suppresses the inhibiting functions of Bcl-2, indicating an ability to induce not only apoptosis but also autophagy. Additionally, a p38-mediated increase in heme oxygenase-1 expression inhibits apoptosis. Moreover, besides inhibiting mammalian target of rapamycin, Akt is associated with decreased Bax expression, thereby acting as both an autophagy inducer and apoptosis inhibitor. Ultimately, manipulation of molecular components involved in autophagy and apoptosis regulation could be targeted as possible therapies for PD.
开发有效的帕金森病（PD）治疗方法需要更好地了解神经退行性变的机制。自噬和细胞凋亡是被认为在 PD 中起关键作用的两种细胞死亡途径。通过鉴定使用治疗化合物改变途径中特定分子成分表达的研究，研究了这些途径之间的分子重叠。Bcl-2 被确定为一种重要的蛋白质，能够通过分别抑制 Beclin-1 和 Bax 来抑制自噬和细胞凋亡。c-Jun N 末端激酶（JNK）和 p38 的参与通过增加 Bax/Bcl-2 比值，在凋亡的激活中是明显的。JNK 介导的磷酸化还抑制 Bcl-2 的抑制功能，表明其不仅能够诱导细胞凋亡，还能够诱导自噬。此外，p38 介导的血红素加氧酶-1 表达增加抑制细胞凋亡。此外，除了抑制哺乳动物雷帕霉素靶蛋白外，Akt 还与 Bax 表达的降低有关，从而充当自噬诱导剂和细胞凋亡抑制剂。最终，对参与自噬和细胞凋亡调节的分子成分的操纵可能成为 PD 的潜在治疗方法。
