A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

神经元蜡样脂质色素沉着症（NCLs；亦统称为Batten病）是一组常染色体隐性溶酶体储存疾病。多达13个基因的突变可导致约10种NCL变异，所有变异均具有重叠的临床症状，包括视力障碍、运动和认知功能障碍、癫痫发作以及早逝。CLN6基因的突变导致一种晚期婴儿期神经元蜡样脂质色素沉着症（vLINCL）的变异形式，以及一种称为A型Kufs的成人发病型疾病。CLN6是一种未知的非糖基化膜蛋白，定位于内质网（ER）。在本研究中，我们对一种自然发生的Cln6突变体（Cln6nclf）小鼠品系进行了详细的表征，以验证其在转化研究中的实用性。我们证明这种Cln6nclf突变导致运动协调、视力、记忆和学习能力下降。病理学上，我们发现皮质特定亚区域和层板中的神经元丢失与行为表型相关。与其他NCL模型类似，该模型表现出皮质和海马体GABA能神经元亚群的特异性丢失，以及早期发生的胶质细胞显著激活。最后，我们证明了记忆和学习的新缺陷，包括大脑皮层树突棘密度的显著减少，这表明在CLN6破坏后，突触强度有所降低。总之，这些发现突出了Cln6nclf小鼠模型与人类NCL患者之间的行为和病理学相似性，验证了该模型作为筛选潜在治疗药物可靠格式的有效性。