Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi 110042, India.
Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi 110042, India.
Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):324-336. doi: 10.1016/j.bbadis.2016.09.010. Epub 2016 Sep 14.
Emerging evidence revealed that abrogated cell cycle entry into highly differentiated mature neurons and muscles is having detrimental consequences in response to cell cycle checkpoints disruption, altered signaling cascades, pathophysiological and external stimuli, for instance, Aβ, Parkin, p-tau, α-synuclein, impairment in TRK, Akt/GSK3β, MAPK/Hsp90, and oxidative stress. These factors, reinitiate undesired cell division by triggering new DNA synthesis, replication, and thus exquisitely forced mature cell to enter into a disturbed and vulnerable state that often leads to death as reported in many neuro- and myodegenerative disorders. A pertinent question arises how to reverse this unwanted pathophysiological phenomenon is attributed to the usage of cell cycle inhibitors to prevent the degradation of crucial cell cycle arresting proteins, cyclin inhibitors, chaperones and E3 ligases. Herein, we identified the major culprits behind the forceful cell cycle re-entry, elucidated the cyclin re-expression based on disturbed signaling mechanisms in neuromuscular degeneration together with plausible therapeutic strategies.
新出现的证据表明，细胞周期进入高度分化的成熟神经元和肌肉的能力被废除，这对细胞周期检查点破坏、信号级联改变、生理病理和外部刺激有不利影响，例如 Aβ、Parkin、p-tau、α-突触核蛋白、TRK、Akt/GSK3β、MAPK/Hsp90 的损伤，以及氧化应激。这些因素通过触发新的 DNA 合成、复制，重新引发不需要的细胞分裂，从而迫使成熟细胞进入一种紊乱和脆弱的状态，正如许多神经和肌肉退行性疾病所报道的那样，这通常导致细胞死亡。一个相关的问题是如何逆转这种不需要的病理生理现象，这归因于使用细胞周期抑制剂来防止关键细胞周期停滞蛋白、周期蛋白抑制剂、伴侣蛋白和 E3 连接酶的降解。在这里，我们确定了导致强制细胞周期重新进入的主要罪魁祸首，阐明了基于神经肌肉退行性变中紊乱的信号机制的周期蛋白重新表达，以及合理的治疗策略。
