Oeckl Patrick, Scheffold Annika, Lechel André, Rudolph K Lenhard, Ferger Boris
aCNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss bInstitute of Molecular Medicine and Max-Planck-Research-Group on Stem Cell Ageing, University of Ulm, Ulm, Germany.
Neuroreport. 2014 Mar 26;25(5):335-9. doi: 10.1097/WNR.0000000000000099.
The most important risk factor for developing Parkinson's disease (PD) is age. Aging is ascribed to different mechanisms, including telomere shortening. Telomeres consist of repetitive DNA sequences and stabilize chromosome integrity. Currently, however, the data reported on telomere shortening in PD patients are inconsistent. We investigated the effect of telomere shortening in the MPTP mouse model of PD using late-generation telomerase-deficient mice (G3 Terc mice). G3 Terc mice showed a reduction in telomere length in nigral tyrosine hydroxylase-positive neurons by 40%, as indicated by quantitative fluorescence in-situ hybridization. There was no difference in the total motor activity and striatal tissue concentrations of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (4-hydroxy-3-methoxyphenylacetic acid), and 3-MT (3-methoxytyramine) concentrations or dopamine turnover in G3 Terc mice in comparison with controls without MPTP treatment. Low-dose MPTP treatment (four injections, 2 h intervals, 2 × 5 and 2 × 7.5 mg/kg) led to a significant decrease in striatal dopamine concentrations that did not differ in G3 Terc mice compared with control mice (19.15 ± 0.44 to 12.81 ± 1.26 ng/mg in control mice in comparison with 19.51 ± 0.59 to 13.56 ± 1.10 ng/mg in G3 Terc mice). In conclusion, telomere shortening does not increase susceptibility to MPTP-induced dopamine depletion in mice. These data indicate that other age-related mechanisms in the brain may play a more important role in enhancing MPTP-induced dopamine depletion.
帕金森病（PD）发病的最重要风险因素是年龄。衰老归因于不同的机制，包括端粒缩短。端粒由重复的DNA序列组成，可稳定染色体完整性。然而，目前关于PD患者端粒缩短的报道数据并不一致。我们使用晚期端粒酶缺陷小鼠（G3 Terc小鼠）在MPTP诱导的PD小鼠模型中研究了端粒缩短的影响。定量荧光原位杂交显示，G3 Terc小鼠黑质酪氨酸羟化酶阳性神经元的端粒长度减少了40%。与未接受MPTP治疗的对照组相比，G3 Terc小鼠的总运动活动、纹状体组织中多巴胺、3,4-二羟基苯乙酸（DOPAC）、4-羟基-3-甲氧基苯乙酸（HVA）和3-甲氧基酪胺（3-MT）的浓度或多巴胺周转率没有差异。低剂量MPTP治疗（四次注射，间隔2小时，2×5和2×7.5 mg/kg）导致纹状体多巴胺浓度显著降低，G3 Terc小鼠与对照小鼠相比无差异（对照小鼠从19.15±0.44降至12.81±1.26 ng/mg，而G3 Terc小鼠从19.51±0.59降至13.56±1.10 ng/mg）。总之，端粒缩短不会增加小鼠对MPTP诱导的多巴胺耗竭的易感性。这些数据表明，大脑中其他与年龄相关的机制可能在增强MPTP诱导的多巴胺耗竭方面发挥更重要的作用。
