Cln6-flox Mouse

Cln6 is a gene encoding a transmembrane protein that resides in the endoplasmic reticulum (ER) [1,2,3,6]. It is involved in the trafficking of lysosomal proteins to the Golgi as part of the CLN6-CLN8 complex (EGRESS), recruiting lysosomal enzymes at the ER for Golgi transfer, thus playing a crucial role in lysosome biogenesis [3]. Mutations in Cln6 are linked to CLN6-related neuronal ceroid lipofuscinoses (NCLs), a group of inherited neurodegenerative diseases [1,2,4,5,6,7].

In nclf mice, a natural mouse model of CLN6-related disease, Cln6 deficiency led to a drastic reduction in the protein amounts of selected lysosomal proteins, many of which were N-glycosylated, soluble hydrolases [1]. This directly linked Cln6 dysfunction to changes in the lysosomal compartment and other NCL forms [1]. In Cln6 mutant mice, a single intracerebroventricular injection of a self-complementary adeno-associated virus serotype 9 vector expressing the human CLN6 gene at post-natal day 1 could prevent or drastically reduce all pathological hallmarks of Batten disease, with significant improvements in motor performance, learning and memory deficits, and survival [8].

In conclusion, Cln6 is essential for the proper trafficking of lysosomal proteins and normal lysosome biogenesis. The study of Cln6 knockout mouse models has significantly advanced our understanding of its role in NCLs, highlighting its potential as a therapeutic target for treating these neurodegenerative disorders [1,8].