Mercado-Ayón Elizabeth, Talgo Ellarie, Flatley Liam, Coulman Jennifer, Lynch David R
Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
Exp Neurol. 2025 Apr;386:115176. doi: 10.1016/j.expneurol.2025.115176. Epub 2025 Feb 2.
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by frataxin deficiency. Neurological deficits remain the ubiquitous feature of FRDA and include progressive ataxia and dysarthria, both of which are controlled to a large degree by the cerebellum. The precise impact of frataxin deficiency on the cerebellum including Purkinje cells remains unclear. In the present work, we examined the biochemical and structural properties of the cerebellum and Purkinje cells in the doxycycline-inducible (FRDAkd) and the Knock-in/Knockout (KIKO) mouse models of FRDA. Acute systemic knockdown of frataxin in FRDAkd mice and chronic frataxin deficiency in KIKO leads to a significant decrease in levels of AMPA receptors, particularly GluR2, and an increase in glial glutamate transporters. Significant astroglial accumulation occurred in KIKO cerebellum but not in FRDAkd mice. Purkinje cell dendritic arbors in the molecular layer did not change compared to wildtype in either model. The Purkinje cell postsynaptic receptor NMDAR1 significantly decreased only in the FRDAkd cerebellum while other NMDA receptor subunits, largely found in non-Purkinje cells, did not change. Overall, we observed dysregulated levels of glutamate receptors and transporters in the KIKO and FRDAkd mice models of Friedreich ataxia, suggesting the importance of frataxin in maintaining Purkinje cells and cerebellar integrity along with synaptic properties. These results point to conserved but not identical synaptic features between the models that may represent markers or conceivably targets in human FRDA.
弗里德赖希共济失调（FRDA）是一种由铁调素缺乏引起的常染色体隐性神经退行性疾病。神经功能缺损是FRDA的普遍特征，包括进行性共济失调和构音障碍，这两者在很大程度上都受小脑控制。铁调素缺乏对包括浦肯野细胞在内的小脑的确切影响尚不清楚。在本研究中，我们检测了多西环素诱导型（FRDAkd）和基因敲入/敲除（KIKO）FRDA小鼠模型中小脑和浦肯野细胞的生化及结构特性。在FRDAkd小鼠中急性全身性敲低铁调素以及在KIKO小鼠中慢性铁调素缺乏导致AMPA受体水平显著降低，尤其是GluR2，同时胶质谷氨酸转运体增加。KIKO小鼠的小脑出现明显的星形胶质细胞堆积，而FRDAkd小鼠则未出现。在这两种模型中，分子层的浦肯野细胞树突分支与野生型相比均未发生变化。浦肯野细胞突触后受体NMDAR1仅在FRDAkd小鼠的小脑中显著降低，而主要存在于非浦肯野细胞中的其他NMDA受体亚基则未发生变化。总体而言，我们在弗里德赖希共济失调的KIKO和FRDAkd小鼠模型中观察到谷氨酸受体和转运体水平失调，这表明铁调素在维持浦肯野细胞和小脑完整性以及突触特性方面具有重要作用。这些结果表明，这些模型之间存在保守但并非完全相同的突触特征，这些特征可能代表人类FRDA中的标志物或潜在靶点。
