Eliseeva Elena, Malik Mohd Yaseen, Minichiello Liliana
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
Biology (Basel). 2024 Aug 20;13(8):637. doi: 10.3390/biology13080637.
In ataxia disorders, motor incoordination (ataxia) is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, decreased BDNF-TrkB signalling appears to contribute to PC dysfunction and ataxia. However, abnormal BDNF-TrkB signalling in granule cells (GCs) may contribute to PC dysfunction and incoordination in ataxia disorders, as TrkB receptors are also present in GCs that provide extensive input to PCs. This study investigated whether dysfunctional BDNF-TrkB signalling restricted to a specific subset of cerebellar GCs can generate ataxia in mice. To address this question, our research focused on mice, in which the TrkB receptor was removed from enkephalinergic precursor-derived cerebellar GCs. We found that deleting , encoding the TrkB receptor, eventually interfered with PC function, leading to ataxia symptoms in the mice without affecting their cerebellar morphology or levels of selected synaptic markers. These findings suggest that dysfunctional BDNF-TrkB signalling in a subset of cerebellar GCs alone is sufficient to trigger ataxia symptoms and may contribute to motor incoordination in disorders like SCA6.
在共济失调性疾病中，运动不协调（共济失调）主要与小脑浦肯野细胞（PCs）的功能障碍和退化有关。例如，在脊髓小脑共济失调6型（SCA6）中，脑源性神经营养因子（BDNF）-酪氨酸激酶受体B（TrkB）信号传导减少似乎导致PC功能障碍和共济失调。然而，颗粒细胞（GCs）中异常的BDNF-TrkB信号传导可能导致共济失调性疾病中的PC功能障碍和不协调，因为TrkB受体也存在于向PCs提供广泛输入的GCs中。本研究调查了仅限于小脑GCs特定亚群的功能失调的BDNF-TrkB信号传导是否会在小鼠中产生共济失调。为了解决这个问题，我们的研究集中在将TrkB受体从小脑脑啡肽能前体衍生的GCs中去除的小鼠身上。我们发现，删除编码TrkB受体的基因最终会干扰PC功能，导致小鼠出现共济失调症状，而不影响其小脑形态或所选突触标记物的水平。这些发现表明，仅小脑GCs亚群中功能失调的BDNF-TrkB信号传导就足以引发共济失调症状，并可能导致SCA6等疾病中的运动不协调。
