C57BL/6JCya-Cln6^em1/Cya

Cln6, associated with Batten disease, encodes a 311-amino-acid transmembrane protein residing in the endoplasmic reticulum (ER) [6]. It is involved in lysosome biogenesis as part of the CLN6-CLN8 complex (EGRESS), which recruits lysosomal enzymes at the ER for Golgi transfer [3]. Dysfunction in Cln6 leads to lysosomal storage disorders, particularly a form of neuronal ceroid lipofuscinoses (NCLs) [1,2,4,5,6,7].

In nclf mice (a natural mouse model for Cln6-related NCL), Cln6 deficiency causes a reduction in the protein amounts of selected lysosomal proteins, many of which are N-glycosylated, soluble hydrolases [1]. In Cln6 mutant mice, a single intracerebroventricular injection of a self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human Cln6 gene at post-natal day 1 prevented or reduced pathological hallmarks of Batten disease, improved motor performance, learning and memory deficits, and extended survival [8].

In conclusion, Cln6 is crucial for lysosome biogenesis by facilitating the transfer of lysosomal enzymes from the ER to the Golgi. Research using Cln6-deficient mouse models has significantly advanced our understanding of Cln6-related NCLs, providing insights into potential therapeutic strategies such as gene therapy [8].

References:

1. Tuermer, Andreas, Mausbach, Simone, Kaade, Edgar, Gieselmann, Volkmar, Thelen, Melanie. 2021. CLN6 deficiency causes selective changes in the lysosomal protein composition. In Proteomics, 21, e2100043. doi:10.1002/pmic.202100043. https://pubmed.ncbi.nlm.nih.gov/34432360/

2. Otero, Maria Gabriela, Kim, Jaemin, Kushwaha, Yogesh Kumar, Salamon, Noriko, Pierson, Tyler Mark. 2024. Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.01.29.577876. https://pubmed.ncbi.nlm.nih.gov/38352418/

3. Bajaj, Lakshya, Sharma, Jaiprakash, di Ronza, Alberto, Schekman, Randy W, Sardiello, Marco. . A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer. In The Journal of clinical investigation, 130, 4118-4132. doi:10.1172/JCI130955. https://pubmed.ncbi.nlm.nih.gov/32597833/

4. Yamashita, Arisa, Shiro, Yuki, Hiraki, Yuri, Yujiri, Takatoshi, Yamazaki, Tetsuo. 2020. Implications of graded reductions in CLN6's anti-aggregate activity for the development of the neuronal ceroid lipofuscinoses. In Biochemical and biophysical research communications, 525, 883-888. doi:10.1016/j.bbrc.2020.03.019. https://pubmed.ncbi.nlm.nih.gov/32171521/

5. Invernizzi, Federica, Castellotti, Barbara, Reale, Chiara, Granata, Tiziana, Canafoglia, Laura. 2024. CLN6-related continuum phenotype caused by aberrant splicing. In Epilepsia open, 10, 348-354. doi:10.1002/epi4.13119. https://pubmed.ncbi.nlm.nih.gov/39718800/

6. Mole, Sara E, Michaux, Gregoire, Codlin, Sandra, Sharp, Julie D, Cutler, Daniel F. . CLN6, which is associated with a lysosomal storage disease, is an endoplasmic reticulum protein. In Experimental cell research, 298, 399-406. doi:. https://pubmed.ncbi.nlm.nih.gov/15265688/

7. Shiro, Yuki, Yamashita, Arisa, Watanabe, Kana, Yamazaki, Tetsuo. . CLN6's luminal tail-mediated functional interference between CLN6 mutants as a novel pathomechanism for the neuronal ceroid lipofuscinoses. In Biomedical research (Tokyo, Japan), 42, 129-138. doi:10.2220/biomedres.42.129. https://pubmed.ncbi.nlm.nih.gov/34380921/

8. Cain, Jacob T, Likhite, Shibi, White, Katherine A, Meyer, Kathrin, Weimer, Jill M. 2019. Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease. In Molecular therapy : the journal of the American Society of Gene Therapy, 27, 1836-1847. doi:10.1016/j.ymthe.2019.06.015. https://pubmed.ncbi.nlm.nih.gov/31331814/