Study Examines Reduction in CLN6’s Ability to Prevent Protein Aggregation

Study Examines Reduction in CLN6’s Ability to Prevent Protein Aggregation
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A reduction in the ability of the CLN6 protein to prevent other proteins from clumping together and forming aggregates can account at least partially for the development of some forms of CLN6 disease.

The study with that finding, “Implications of graded reductions in CLN6’s anti-aggregate activity forthe development of the neuronal ceroid lipofuscinoses,” was published in the journal Biochemical and Biophysical Communications.

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, comprise a group of childhood neurodegenerative disorders. These conditions can be caused by mutations in 14 genes (CLN1 to CLN14), all of which lead to the accumulation of toxic insoluble waste deposits, called lipofuscins, inside cells.

One of these genes is CLN6, which provides instructions to make the CLN6 protein. Mutations in CLN6 have been linked to a particular type of NCL, called CLN6 disease, which comprises both late infantile- and adult-onset disease subtypes.

The molecular mechanisms underlying CLN6 disease remain largely unknown, mainly due to the lack of information regarding the role of the CLN6 protein in the body.

In a previous study, the same group of researchers showed that CLN6 can prevent other proteins from forming aggregates. “This finding led us to hypothesize that dysfunction of CLN6 causes a buildup of protein aggregates, leading to the development of CLN6 disease,” researchers wrote.

To test this idea, investigators created several versions of the CLN6 protein containing mutations in a particular region of the protein that is thought to be important for its anti-protein aggregate function.

They then compared the ability these mutant versions of CLN6 had to prevent the aggregation of four different alpha B-crystallin (αBC) mutant proteins that are very prone to aggregation. They also did the same tests with the normal version of CLN6, which served as a control for comparison.

Results showed that one of the versions of the CLN6 protein (rg106ProfsX) containing a mutation equivalent to that found in a mouse model of late infantile-onset CLN6 disease (nclf mutant) failed to prevent αBC mutant proteins from clumping together.

In contrast, two other mutant versions of the CLN6 protein containing mutations associated with the adult-onset form of the disease successfully prevented the aggregation of αBC proteins. While one of these CLN6 mutants (Arg149Cys) was found to prevent the aggregation of two types of αBC mutants, the other (Arg149His) did so in all four.

Both mutations led to the substitution of the amino acid arginine in the same position of the protein sequence by cysteine in one case, and by histidine in the other. (Amino acids are the building blocks of proteins.) Based on these observations researchers suggested that CLN6’s anti-aggregate activity seems to be controlled by the specific amino acid changes taking place at specific positions within its sequence.

“The success in countering the four αBC mutants, however, does not necessarily guarantee that a full range of CLN6’s targets can avoid aggregating in patients [carrying distinct mutations on each CLN6 gene copy],” they wrote.

For that reason, investigators do not discard that additional “defects in as-yet-unidentified CLN6’s functions,” other than a reduction in its anti-aggregate activity, could be contributing to the development of CLN6 disease, and may be the reason why the disease manifests itself at different ages.

Nevertheless, they propose “that the graded reduction in CLN6’s anti-aggregate activity governs the clinical course of late infantile- and adult-onset NCL.”

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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