Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner

Kristina Oresic, Britta Mueller, Domenico Tortorella

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NCLs (neuronal ceroid lipofuscinoses), a group of inherited neurodegenerative lysosomal storage diseases that predominantly affect children, are the result of autosomal recessive mutations within one of the nine cln genes. The wild-type cln gene products are composed of membrane and soluble proteins that localize to the lysosome or the ER (endoplasmic reticulum). However, the destiny of the CIn variants has not been fully characterized. To explore a possible link between ER quality control and processing of CIn mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6G123D and Cln6M241T) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most probably generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6G123D and Cln6 M241T polypeptides. The results implicate ER quality control in the instability of the CIn variants that probably contributes to the development of NCL.

Original languageEnglish
Pages (from-to)173-181
Number of pages9
JournalBioscience Reports
Issue number3
StatePublished - Jun 2009


  • Derlin 1
  • Endoplasmic reticulum quality control
  • Endoplasmic-reticulum- associated degradation (ERAD)
  • Genetic disease
  • Misfolded membrane protein
  • sel-1 suppressor of lin-12-like (Caenorhabditis elegans) (SEL1L)


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