Implications of graded reductions in CLN6’s anti-aggregate activity for the development of the neuronal ceroid lipofuscinoses

• Published in: Biochemical and biophysical research communications Vol. 525; no. 4; pp. 883 - 888
• Main Authors: Yamashita, Arisa, Shiro, Yuki, Hiraki, Yuri, Yujiri, Takatoshi, Yamazaki, Tetsuo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-05-2020
• Subjects: Amino Acid Substitution; CLN6; HeLa Cells; Humans; Kufs; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mutation; NCL; Neuronal Ceroid-Lipofuscinoses - genetics; Neuronal Ceroid-Lipofuscinoses - pathology; Kufs; ER; NCL; CLN6
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.03.019

CLN6, spanning the endoplasmic reticulum membrane, is a protein of unknown function. Mutations in the CLN6 gene are linked to an autosomal recessively inherited disorder termed CLN6 disease, classified as a form of the neuronal ceroid lipofuscinoses (NCL). The pathogenesis of CLN6 disease remains poorly understood due to a lack of information about physiological roles CLN6 plays. We previously demonstrated that CLN6 has the ability to prevent protein aggregate formation, and thus hypothesized that the abrogation of CLN6’s anti-aggregate activity underlies the development of CLN6 disease. To test this hypothesis, we narrowed down the region vital for CLN6’s anti-aggregate activity, and subsequently investigated if pathogenic mutations within the region attenuate CLN6’s anti-aggregate activity toward four aggregation-prone αB-crystallin (αBC) mutants. None of the four αBC mutants was prevented from aggregating by the Arg106ProfsX truncated CLN6 mutant, the human counterpart of the nclf mutant identified in a naturally occurring mouse model of late infantile-onset CLN6 disease. In contrast, the Arg149Cys and the Arg149His CLN6 mutants, both associated with adult-onset CLN6 disease, blocked aggregation of two out of and all of the four αBC mutants, respectively, indicating that CLN6’s anti-aggregate activity is differentially modulated according to the substitution pattern at the same amino acid position. Collectively, we here propose that the graded reduction in CLN6’s anti-aggregate activity governs the clinical course of late infantile- and adult-onset NCL.
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•Impairment of CLN6’s anti-aggregate activity would cause CLN6 disease, a form of the neuronal ceroid lipofuscinoses (NCL).•The anti-aggregate activity was reduced in a graded manner according to pathogenic mutations in the CLN6 gene.•Graded reductions in the anti-aggregate activity would governs the clinical course of NCL.•CLN6 disease can also be categorized as a protein aggregate disease.