Deneubourg Celine, Salimi Dafsari Hormos, Lowe Simon, Martinez-Cotrina Aitana, Mazaud David, Park Seo Hyun, Vergani Virginia, Almacellas Barbanoj Amanda, Maroofian Reza, Averdunk Luisa, Ghayoor-Karimiani Ehsan, Jayawant Sandeep, Mignot Cyril, Keren Boris, Peters Renate, Kamath Arveen, Mattas Lauren, Verma Sumit, Silwal Arpana, Distelmaier Felix, Houlden Henry, Lignani Gabriele, Antebi Adam, Jepson James, Jungbluth Heinz, Fanto Manolis
Department of Basic and Clinical Neuroscience, King's College London, London, United Kingdom.
Department of Paediatric Neurology, Evelina's London Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom.
Autophagy. 2025 Feb;21(2):447-459. doi: 10.1080/15548627.2024.2405956. Epub 2024 Oct 10.
Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 () gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with predictions.: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; : ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; : TSC complex; VS: Vici syndrome.
癫痫是一种常见的神经系统疾病，由后天或先天性疾病导致的神经元回路控制功能失调引起。自噬是一种重要的神经元清理机制，受损时会导致严重的蛋白毒性应激。自噬功能障碍已通过多种分子机制与癫痫发生相关联。维西综合征（VS）是人类典型的先天性自噬障碍，由于异位P颗粒自噬栓系因子5（）基因的隐性变异，该基因对自噬体 - 溶酶体融合和自噬清除至关重要。在这里，我们使用来研究Epg5在发育、衰老和癫痫发作中的重要性。我们的数据表明，自噬清除受损导致的蛋白毒性应激与癫痫样行为相关且共同受到调节，这表明癫痫发作是蛋白毒性应激和年龄依赖性神经退行性进展的直接后果。我们从EPG5突变患者那里提供了补充证据，证明了与预测一致的癫痫表型。：AD：阿尔茨海默病；ALS - FTD：肌萎缩侧索硬化 - 额颞叶痴呆；DART：觉醒追踪；ECoG：皮质电图；EEG：脑电图；：异位P颗粒5自噬栓系因子；KA：红藻氨酸；MBs：蘑菇体；MRI：磁共振成像；MTOR：雷帕霉素激酶机制靶点；PD：帕金森病；：TSC复合物；VS：维西综合征。
