CLN7, the protein lacking CLN7 Batten disease, is involved not only in the functioning of lysosomes (the cell compartment responsible for breaking down waste) but also in communication between nerve and muscle cells, according to a preclinical study.
These findings open the possibility that proteins associated with other types of Batten disease, which are also linked to lysosomes, may have alternate locations and functions in nerve cells.
The study, “The neuronal ceroid lipofuscinosis protein Cln7 works in the postsynaptic cell to regulate synapse development, â€Was published in the journal Scientific reports.
Batten’s disease, also known as neuronal ceroid lipofuscinosis (NCL), is the most common group of pediatric neurodegenerative disorders. It is associated with a toxic accumulation of lipofuscins (deposits of fat and protein) inside lysosomes, which is particularly harmful to brain cells, leading to nerve cell damage and death.
CLN7 disease, a rare form of Batten disease in late childhood, is characterized by seizures, visual decline, loss of previously acquired skills, speech impairment, and mental and motor deterioration, with onset illness between 1.5 and 5 years.
The disease is caused by mutations in the CLN7 /MFSD8 gene, which leads to the production of a defective CLN7 protein. CLN7 is known to be mainly localized on the surface of lysosomes and involved in the regulation of several lysosomal proteins and the activation of a major signaling complex called TORC1.
However, growing evidence suggests that CLN7 is also present at the synapse of nerve cells (neurons) and that the mutations associated with Batten disease cause synaptic dysfunction. The synapse is the small space between nerve cells (neurons), or between a neuron and a muscle cell – a special synapse called a neuromuscular junction – that allows the transmission of electrical or chemical messages between them.
In the study, British researchers, working with colleagues in Canada, found that CLN7 is also involved in the normal development of synapses and in communication between nerve and muscle cells.
They first generated a new CLN7 disease model using the fruit fly Drosophila, a validated genetic model. Next, the team used this model to assess whether CLN7 had function at the neuromuscular junction, a synapse model commonly used to study the function of proteins associated with neurological diseases.
The results showed that the growth of the neuromuscular junction in these fruit flies was impaired, leading to reduced synaptic function and motor changes.
Further analysis revealed that the CLN7 protein was normally located inside specific vesicles on the postsynaptic side of the junction – the muscle cell – where it interacted with the TORC1 activator, Rheb, to regulate TORC1 signaling. TORC1 is involved in the regulation of neuronal growth and development.
These results indicate that a defective CLN7 protein causes a deregulation of TORC1 activity in postsynaptic muscle cells, suggesting “an involvement of CLN7 in the regulation of the trans-synaptic communication necessary for the normal development of synapses”, have writes the researchers.
“We propose that late childhood NCL may be the consequence of early synapse development failure caused by dysfunctional TORC signaling,” they added.
The team stressed that future studies are needed to better understand the interactions between CLN7 and Rheb and its underlying effects in TORC1 activity.
“Potentially, alternative locations for CLN proteins in vivo in the [brain and spinal cord] may be an important part of the emerging history of synaptic dysfunction in NCL, â€the researchers wrote.
