A type of Batten disease, called CLN8 disease, is associated with the failure of important cell- signaling molecules to properly interact and engage in critical signaling pathways, according to results of a recent study.
The study, “Neuronal ceroid lipofuscinosis related ER membrane protein CLN8 regulates PP2A activity and ceramide levels,” was published in the journal BBA Molecular Basis of Disease.
Neuronal ceroid lipofuscinosis (NCL) — also called Batten disease — are a group of neurodegenerative lysosomal disorders that predominantly affect children and lead to severe pathological conditions such as progressive loss of motor neuron function, loss of vision, diminished mental capacity, epilepsy, ataxia, and eventually premature death.
Thirteen genetically distinct subtypes of NCLs have been identified to date, each gene encoding a variety of unrelated proteins called ceroidlipofuscinosis neuronal proteins (CLNs) that are localized to various partitions of cells.
One NCL disorder subtype known as CLN8 disease is caused by a deficiency in the gene CLN8. The function of the CLN8 protein is unknown, but it appears to reside in a cell structure called the endoplasmic reticulum (ER), which generates much of the cell’s proteins and lipids (e.g. fatty acids, oils, waxes, steroids, and triglycerides) and has been suggested to play a role in processing ceramides — a family of lipids that make up the membranes of cells.
Researchers from Kansas State University sought to clarify the function of CLN8 in healthy cells and its role in CLN8 disease.
The authors identified two molecules, PP2A and its biological inhibitor I2PP2A, as interacting proteins of CLN8. PP2A is an enzyme known as a phosphatase and it governs a wide range of pathways by regulating critical signaling molecules through dephosphorylation — the removal of modifying phosphate molecules to turn signals on or off.
Researchers saw that the dephosphorylation levels of PP2A targets were increased in CLN8 disease patients’ cells, suggesting higher PP2A activity in cells lacking CLN8. The researchers showed this reduction can be reversed by inhibiting PP2A activity, which could have implications for understanding and treating CLN8 disease.
Since ceramides have been shown to bind and influence the activity of PP2A and I2PP2A, the team further examined whether ceramide levels in CLN8-deficient cells were changed. Interestingly, ceramide levels were reduced by 60% in CLN8 disease patients’ cells compared to controls.
The researchers suggest a model where ceramide availability in the presence of CLN8, as in healthy patients, potentially recruits I2PP2A and PP2A to inactivate PP2A dephosphorylation activity. In CLN8 disease patients with ceramide and CLN8 deficiency, the CLN8-ceramide hub at the ER membrane does not form, the sequestration of PP2a and its inhibitor I2PP2A is reduced, and, ultimately, PP2A dephosphorylation activity increases.
CLN8 has also been identified as having a potential role in another rare disorder, Gaucher disease (GD). Some patients with milder forms of GD have higher levels of CLN8 than healthy patients, so researchers proposed that increased CLN8 levels influence GD patient cells in another way than CLN8 disease (where CLN8 is deficient).
They suggest that more CLN8 may increase the level of ceramides and rebalance the lipid level maintenance in GD patients, but that further investigation will be needed to comprehend the exact relationship between CLN8 and GD.
“Further studies to dissect the interactions between these proteins will help to elucidate the mechanism by which the PP2A activity is regulated in the CLN8-ceramide hub,” researchers said. “PP2A, as well as its targeting [enzymes], have been implicated in neuronal development. In addition, dysregulation of PP2A activity has been reported in neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. It is possible that altered PP2A activity may also contribute to neuronal defects in CLN8 disease.”