Division of Human Genetics, Department of Pediatrics.
Department of Pathology and Laboratory Medicine.
JCI Insight. 2019 Nov 1;4(21):131961. doi: 10.1172/jci.insight.131961.
Accumulation of lysosomal storage material and late-stage neurodegeneration are hallmarks of lysosomal storage disorders (LSDs) affecting the brain. Yet, for most LSDs, including CLN3 disease, the most common form of childhood dementia, it is unclear what mechanisms drive neurologic symptoms. Do deficits arise from loss of function of the mutated protein or toxicity from storage accumulation? Here, using in vitro voltage-sensitive dye imaging and in vivo electrophysiology, we find progressive hippocampal dysfunction occurs before notable lysosomal storage and neuronal loss in 2 CLN3 disease mouse models. Pharmacologic reversal of lysosomal storage deposition in young mice does not rescue this circuit dysfunction. Additionally, we find that CLN3 disease mice lose an electrophysiologic marker of new memory encoding - hippocampal sharp-wave ripples. This discovery, which is also seen in Alzheimer's disease, suggests the possibility of a shared electrophysiologic signature of dementia. Overall, our data describe new insights into previously unknown network-level changes occurring in LSDs affecting the central nervous system and highlight the need for new therapeutic interventions targeting early circuit defects.
溶酶体储存物质的积累和晚期神经退行性变是影响大脑的溶酶体储存障碍（LSD）的标志。然而，对于大多数 LSD，包括 CLN3 病，最常见的儿童痴呆形式，尚不清楚是什么机制导致了神经症状。是由于突变蛋白的功能丧失还是由于储存积累的毒性导致的？在这里，我们使用体外电压敏感染料成像和体内电生理学，发现 2 种 CLN3 疾病小鼠模型中，在明显的溶酶体储存和神经元丢失之前，就出现了进行性海马功能障碍。在年轻小鼠中用药物逆转溶酶体储存沉积并不能挽救这种回路功能障碍。此外，我们发现 CLN3 疾病小鼠失去了新记忆编码的电生理标志物 - 海马尖波涟漪。这一发现也见于阿尔茨海默病，表明痴呆症可能具有共同的电生理特征。总的来说，我们的数据描述了对影响中枢神经系统的 LSD 中以前未知的网络水平变化的新见解，并强调了需要针对早期回路缺陷的新治疗干预措施。
