Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
Trends Mol Med. 2018 Jan;24(1):18-29. doi: 10.1016/j.molmed.2017.11.006. Epub 2017 Dec 9.
Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction. The range of candidates might address the need for region-, cell-, or even cellular compartment-specific modulation. Given the array of clinical and experimental drugs targeting cAMP/cGMP signaling, we propose that proteasome activators targeting secondary messengers might be exploited as novel agents for the treatment or prevention of some neurodegenerative diseases.
错误折叠的蛋白质聚集体可能会损害 26S 蛋白酶体复合物的功能，使神经元易受加速和受损的蛋白质平衡的影响，从而导致神经退行性变的发病机制。通过磷酸化关键亚基表位来增强 26S 蛋白酶体功能的策略已被证明可有效减少疾病小鼠模型中的蛋白质聚集体。我们讨论了磷酸二酯酶 (PDE) 抑制剂和 G 蛋白偶联受体 (GPCR) 靶向药物如何被视为候选治疗药物，作用于第二信使信号转导。候选药物的范围可能需要针对区域、细胞甚至细胞区室的特异性调节。鉴于针对 cAMP/cGMP 信号的大量临床和实验药物，我们提出针对二级信使的蛋白酶体激活剂可能被用作治疗或预防某些神经退行性疾病的新型药物。
