聚合酶I(PolI)位于核糖体RNA(rRNA)合成的中心。PolI是治疗癌症的靶标。鉴于癌症和神经变性之间的许多细胞共性(即,同一枚硬币的不同面),考虑瞄准PolI或,更一般地说,rRNA合成用于治疗与终末分化神经元死亡相关的疾病。原则上,核糖体合成蛋白质,and,因此,PolI可以被认为是蛋白质合成的起点。鉴于异常蛋白质如α-突触核蛋白和tau的细胞积累是神经退行性疾病如帕金森病和额颞叶痴呆的基本特征,减少蛋白质产生现在被认为是治疗这些和密切相关的神经退行性疾病的可行目标。聚合酶I活性和rRNA产生的异常也可能与核和核仁应激有关,DNA损伤,和童年开始的神经元死亡,UBTFE210K神经回归综合征也是如此。此外,抑制PolI的活性可能是减缓衰老的可行策略。在开始使用PolI抑制治疗神经系统非癌性疾病之前,必须回答许多问题。首先,神经元能耐受多少PolI抑制,以及多长时间?PolI的抑制应该是连续的还是脉冲的?细胞会通过上调活性rDNA的数量来补偿PolI的抑制吗?目前,我们对阿尔茨海默病没有有效和安全的疾病调节疗法,α-突触核蛋白病,或者tau蛋白病,必须探索新的治疗目标和方法。
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.