CLN3 Deficiency Leads to Abnormalities in Cellular Recycling Process, Study Shows

The CLN3 gene may play a more crucial role than previously thought in the normal balance of cellular recycling processes and the degradation of important fatty molecules in nervous brain cells, a study suggests.

The study titled, “Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking,” was published in the Journal of Biological Chemistry.

Cells require constant recycling of cellular components so they can keep healthy, but they also use degraded products to produce new components. This is an essential process for life that, when disrupted, can lead to cell damage or death, and even promote the development of diseases.

Lysosomes are tiny vesicles that play a crucial role in this recycling/degradation process. There are more than 60 different enzymes and proteins that can be in these lysosomes, which are responsible for degrading various cellular components, such as proteins, fats, and sugars.

“The physiological importance of lysosomal homeostasis [balance] is demonstrated by the existence of numerous diseases that are caused by mutations in genes that code for lysosomal proteins, which result in general lysosomal dysfunction associated with accumulation of non-degraded materials lysosome,” the researchers stated.

Mutations in the CLN3 gene, which codes for a protein that is part of the lysosomal membrane, lead to the development of lysosomal storage disorder CLN3 — one type of Batten disease.

This illness is mostly characterized by degeneration of neurons, or nervous brain cells. However, the mechanisms that underlie this process remain unclear.

To gain insight into CLN3-related neurodegenerative mechanisms, researchers performed a type of experiment known as mass spectrometry on isolated lysosomes from the cerebellum (a region of the brain) of healthy mice and genetically engineered mice with CLN3 disease. With this particular experimental approach, the team could accurately identify the different chemical components that were comprised in lysosomes.

The researchers found that the amount of 28 lysosomal enzymes was significantly reduced in CLN3 mice compared to healthy controls. In particular, 11 of these enzymes were found to be involved in the degradation of a class of fat molecules, called lactosylceramides and glycosphingolipids.

Lower levels of these fat-degrading enzymes were found to be correlated with several alterations in the distribution and composition of cellular membranes, as they rely on the recycling of fat molecules.

In particular, CLN3-defective cells showed low levels of lactosylceramides and glycosphingolipids due to their impaired degradation and recycling process.

The team believes these findings indicate “that Cln3 has a more generalized role in cellular and in particular lysosomal homeostasis than previously recognized.”

“Our findings suggest that CLN3 has a crucial role in regulating lysosome composition and their function, particularly in degrading of sphingolipids, and, as a consequence, in membrane transport along the recycling endosome pathway,” the researchers said.