Mutations in the gene CLN5which cause a form of late childhood Batten disease, disrupt the functioning and movement of cell compartments called lysosomes, the so-called “recycling centers” of cells.
This is according to the studyDeficiency of lysosomal protein CLN5 alters lysosomal function and movement», published in September in the magazine Biomolecules.
Lysosomes are cellular compartments that act as “recycling centers”, breaking down large, complex molecules into their building blocks, which can then be reused in the cell. Lysosomes contain a number of specialized enzymes which are used to break down different molecules and also tend to maintain a relatively acidic environment to facilitate this breakdown.
Impaired lysosome function is characteristic of all forms of Batten disease at the cellular level, including Batten disease caused by CLN5 mutations (sometimes just called CLN5 disease). However, the precise function of the CLN5 gene, and the ways in which lysosomes are dysregulated when the gene is mutated, remain incompletely understood.
To find out more, a team led by New Zealand scientists conducted a series of studies using neurons derived from induced pluripotent stem cells (iPSCs). Basically, it involves taking human cells (usually skin or blood cells) and then “reverse-engineering” those cells into iPSC, a type of stem cell capable of developing into other cell types when it receives the right biochemical signals.
Here, the iPSCs received signals to prompt them to develop into neurons (nerve cells). The team then used a genetic engineering technique called CRISPR to create mutations in the CLN5 gene in some of the cells, and performed a battery of analyzes to see how these mutations affected lysosome function.
The results revealed that CLN5 the mutations did not change the overall size of lysosomes in the cells, but cells with these mutations had fewer acidic compartments and also reduced the activity of cathepsin B, a lysosomal enzyme used to break down complex proteins.
“Our results suggest that reduction of acidic organelles (lysosomes) in CLN5-deficient human neurons possibly leads to reduced activity of lysosomal cathepsin B in the [CLN5-deficient] neurons compared to control neurons,” the researchers wrote.
Neurons are large and complex cells, and under normal circumstances a lysosome is not just found in one location within the cell – rather these cellular compartments are constantly in motion, transported to different cellular locations to support the various activities of the cell. cell. In other imaging studies, the researchers demonstrated that CLN5-deficient neurons showed marked reductions in lysosome movement.
“From our data, it appears that the anterograde [toward-the-front] lysosomal movement is impaired in CLN5-deficient human neurons,” the researchers wrote. The backward lysosomal movement of the cell (retrograde movement) showed a similar trend, although the results did not reach statistical significance.
The team noted that impaired lysosomal movement “has never been reported in CLN5 Batten disease,” adding “it will be interesting to test whether other forms of Batten disease as well as other neurodegenerative diseases exhibit such lysosomal trafficking abnormalities.”