Department of Pathological Physiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, 323 00 Pilsen, Czech Republic; Laboratory of Neurodegenerative Disorders, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody7 76, 323 00 Pilsen, Czech Republic.
Neurosci Lett. 2020 Apr 23;725:134870. doi: 10.1016/j.neulet.2020.134870. Epub 2020 Feb 25.
Hereditary cerebellar degenerations are severe and complex diseases for which there is currently no effective causal treatment. A hopeful method could be the support of plasticity or neurotransplantation. However, there are still many unknown aspects which could influence the outcome of treatment. As neurotrophic factors are essential in neuroplasticity and neuronal integration, potential abnormalities in their levels could be involved in the pathogenesis of the disease and would possibly explain the unsuitability of diseased cerebellum for the graft integration. The aim of this study was to identify and compare basal levels of trophic factors BDNF and GDNF in the cerebellum in two mouse models of cerebellar degeneration - Lurcher and pcd. Basal levels of BDNF in the cerebellum have been shown to be lower in both mutant models than in healthy controls. However, the GDNF levels were surprisingly increased in the cerebella of Lurcher mutant mice compared to both wild type and pcd mice. In addition, a different distribution of GFAP-positive cells in the cerebellum was revealed in Lurcher mice. These differences suggest that the niche of the Lurcher mutant cerebellum is changed. The question, however, remains how these changes are related to the neurodegenerative process and how they could influence potential compensatory mechanisms, plasticity and response to therapeutic interventions.
遗传性小脑退行性疾病严重且复杂，目前尚无有效的病因治疗方法。有希望的方法可能是支持可塑性或神经移植。然而，仍有许多未知的方面可能会影响治疗效果。由于神经营养因子在神经可塑性和神经元整合中至关重要，因此其水平的潜在异常可能与疾病的发病机制有关，并可能解释为何病变的小脑不适合移植整合。本研究的目的是在两种小脑退行性变的小鼠模型——Lurcher 和 pcd 中，鉴定和比较小脑内神经营养因子 BDNF 和 GDNF 的基础水平。研究表明，两种突变模型的小脑内 BDNF 基础水平均低于健康对照组。然而，令人惊讶的是，与野生型和 pcd 小鼠相比，Lurcher 突变小鼠的小脑内 GDNF 水平显著升高。此外，在 Lurcher 小鼠的小脑内还揭示了 GFAP 阳性细胞的不同分布。这些差异表明 Lurcher 突变小脑的生态位发生了改变。然而，问题仍然是这些变化与神经退行性过程有何关系，以及它们如何影响潜在的代偿机制、可塑性和对治疗干预的反应。
