Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end-stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto-occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end-stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near-linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep—presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)—beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.

中文翻译：

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绵羊 CLN5 和 CLN6 神经元蜡样脂褐质病（巴顿病）的神经病理学特征

患有天然存在的 CLN5 和 CLN6 形式的神经元蜡样脂褐质病（巴顿病）的绵羊具有人类疾病的关键临床特征，并且代表了开发和测试基因疗法临床功效的理想模型系统。然而，首先重要的是要描述受影响绵羊疾病进展过程中发生的神经病理学变化。这项研究比较了 CLN5 影响的 Borderdale 羊、CLN6 影响的南汉普郡羊和美利奴羊大脑从出生到 ≤24 月龄的终末期疾病的神经变性、神经炎症和溶酶体储存积累。尽管基因产物、突变和亚细胞定位非常不同，但所有三种疾病模型的致病级联非常相似。受影响的绵羊出生时就存在神经胶质激活，并且先于神经元损失，两者从与临床症状最显着相关的视觉皮质和顶枕皮质扩散到终末期疾病的整个皮质套。相比之下，皮层下区域参与较少，但随着年龄的增长，患病羊大脑中的溶酶体储存量几乎呈线性增加。这些神经病理学变化与已发表的临床数据的相关性确定了受影响绵羊的三个潜在治疗窗口——症状前（3个月）、早期症状（6个月）和晚期症状疾病阶段（9个月大）——超过这些时间，神经病理学的广泛耗竭神经元可能会减少任何治疗效果的机会。绵羊 CLN5 和 CLN6 疾病神经病理学变化的全面自然史对于确定治疗对每个疾病阶段的影响至关重要。