Wellcome Centre for Mitochondrial Research, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Acta Neuropathol Commun. 2023 May 31;11(1):86. doi: 10.1186/s40478-023-01579-w.
Refractory epilepsy is the main neurological manifestation of Alpers' syndrome, a severe childhood-onset mitochondrial disease caused by bi-allelic pathogenic variants in the mitochondrial DNA (mtDNA) polymerase gamma gene (POLG). The pathophysiological mechanisms underpinning neuronal hyperexcitabilty leading to seizures in Alpers' syndrome remain unknown. However, pathological changes to reactive astrocytes are hypothesised to exacerbate neural dysfunction and seizure-associated cortical activity in POLG-related disease. Therefore, we sought to phenotypically characterise astrocytic pathology in Alpers' syndrome. We performed a detailed quantitative investigation of reactive astrocytes in post-mortem neocortical tissues from thirteen patients with Alpers' syndrome, eight neurologically normal controls and five sudden unexpected death in epilepsy (SUDEP) patients, to control for generalised epilepsy-associated astrocytic pathology. Immunohistochemistry to identify glial fibrillary acidic protein (GFAP)-reactive astrocytes revealed striking reactive astrogliosis localised to the primary visual cortex of Alpers' syndrome tissues, characterised by abnormal-appearing hypertrophic astrocytes. Phenotypic characterisation of individual GFAP-reactive astrocytes demonstrated decreased abundance of mitochondrial oxidative phosphorylation (OXPHOS) proteins and altered expression of key astrocytic proteins including Kir4.1 (subunit of the inwardly rectifying K ion channel), AQP4 (astrocytic water channel) and glutamine synthetase (enzyme that metabolises glutamate). These phenotypic astrocytic changes were typically different from the pathology observed in SUDEP tissues, suggesting alternative mechanisms of astrocytic dysfunction between these epilepsies. Crucially, our findings provide further evidence of occipital lobe involvement in Alpers' syndrome and support the involvement of reactive astrocytes in the pathogenesis of POLG-related disease.
难治性癫痫是 Alpers 综合征的主要神经表现，Alpers 综合征是一种严重的儿童起病的线粒体疾病，由线粒体 DNA（mtDNA）聚合酶γ基因（POLG）的双等位致病性变异引起。导致 Alpers 综合征中癫痫发作的神经元过度兴奋的病理生理机制尚不清楚。然而，推测反应性星形胶质细胞的病理变化会加剧神经功能障碍和与 POLG 相关疾病中的癫痫相关皮质活动。因此，我们试图对 Alpers 综合征中的星形胶质细胞病理学进行表型特征分析。我们对 13 名 Alpers 综合征患者、8 名神经正常对照者和 5 名癫痫猝死（SUDEP）患者的死后新皮质组织进行了详细的定量研究，以控制一般癫痫相关的星形胶质细胞病理学。针对胶质纤维酸性蛋白（GFAP）反应性星形胶质细胞的免疫组织化学显示，Alpers 综合征组织的初级视觉皮层局部存在明显的反应性星形胶质增生，其特征是异常的肥大星形胶质细胞。对个体 GFAP 反应性星形胶质细胞的表型特征分析表明，线粒体氧化磷酸化（OXPHOS）蛋白的丰度降低，关键星形胶质细胞蛋白的表达发生改变，包括 Kir4.1（内向整流 K 离子通道的亚基）、AQP4（星形胶质细胞水通道）和谷氨酰胺合成酶（代谢谷氨酸的酶）。这些表型星形胶质细胞的变化通常与 SUDEP 组织中的病理学不同，这表明这两种癫痫之间存在不同的星形胶质细胞功能障碍机制。至关重要的是，我们的发现提供了更多证据表明 Alpers 综合征中涉及枕叶，并支持反应性星形胶质细胞在 POLG 相关疾病发病机制中的参与。
