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A reduction in the ability of the CLN6 protein to prevent other proteins from sticking together and forming aggregates may at least partially explain the development of some forms of CLN6 disease.

The study with this conclusion, “Implications of progressive reductions in CLN6 anti-aggregation activity for the development of neuronal ceroid lipofuscinoseswas published in the journal Biochemical and biophysical communications.

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

One of these genes is CLN6, which provides instructions for making the CLN6 protein. Mutations in CLN6 have been linked to a particular type of NCL, called CLN6 disease, which includes both late childhood and adult 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 CLN6 dysfunction causes an accumulation of protein aggregates, leading to the development of CLN6 disease,” the researchers wrote.

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

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

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

In contrast, two other mutant versions of the CLN6 protein containing mutations associated with the adult form of the disease successfully prevented αBC protein aggregation. While one of these CLN6 mutants (Arg149Cys) was found to prevent 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 at 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, the researchers suggested that the anti-aggregation activity of CLN6 appears to be controlled by the specific amino acid changes that occur at specific positions in its sequence.

“However, success in combating the four αBC mutants does not necessarily guarantee that a full range of CLN6 targets can avoid aggregation in patients. [carrying distinct mutations on each CLN6 gene copy],” they wrote.

For this reason, the investigators do not rule out that other “defects in the functions of yet unidentified CLN6”, other than a reduction in its anti-aggregating activity, could contribute to the development of CLN6 disease, and may be the reason why the disease manifests itself at different ages.

Nevertheless, they propose “that the gradual reduction in the anti-aggregating activity of CLN6 governs the clinical course of late-onset NCL in children and adults.”