👤 Elena K Shematorova

The neuronal ceroid lipofuscinoses (NCLs) collectively constitute one of the most common forms of inherited childhood-onset neurodegenerative disorders. They form a heterogeneous group of incurable lysosomal storage diseases that lead to blindness, motor deterioration, epilepsy, and dementia. Traditionally the NCL diseases were classified according to the age of disease onset (infantile, late-infantile, juvenile, and adult forms), with at least 13 different NCL varieties having been described at present. The current review focuses on classic juvenile NCL (JNCL) or the so-called Batten (Batten-Spielmeyer-Vogt; Spielmeyer-Sjogren) disease, which represents the most common and the most studied form of NCL, and is caused by mutations in the Show less

Mutations in the CLN3 gene lead to so far an incurable juvenile-onset neuronal ceroid lipofuscinosis (JNCL) or Batten disease that starts at the age of 4-6 years with a progressive retinopathy leading to blindness. Motor disturbances, epilepsy and dementia manifest during several following years. Most JNCL patients carry the same 1.02-kb deletion in the CLN3 gene, encoding an unusual transmembrane protein, CLN3 or battenin. Based on data of genome-wide expression profiling in CLN3 patients with different rate of the disease progression [Mol. Med., 2011, 17: 1253-1261] and our bioinformatic analysis of battenin protein-protein interactions in neurons we propose that CLN3 can function as a molecular chaperone for some plasma membrane proteins, being crucially important for their correct folding in endoplasmic reticulum. Changes in spatial structure of these membrane proteins lead to transactivation of the located nearby receptors. Particularly, CLN3 interacts with a subunit of Na/K ATPase ATP1A1 which changes its conformation and activates the adjacent epidermal growth factor receptor (EGFR). As a result, a large amount of erroneously activated EGFR generates MAPK signal cascades (ERK1/ERK2, JNKs and p38) from cell surface eventually causing neurons' death. Molecular mechanism of the juvenile form of Batten disease (JNCL), which is based on the excessive activation of signaling cascades in a time of the radical increase of neuronal membranes' area in the growing brain, have been proposed and substantiated. The primary cause of this phenomenon is the defective function of the CLN3 protein that could not act properly as molecular chaperone for some plasma membrane proteins in the endoplasmic reticulum. The incorrect three-dimensional structure of at least one such protein, ATP1A1, leads to unregulated spontaneous and repetitive activation of the SRC kinase that transactivates EGFR with the subsequent uncontrolled launch of various MAPK cascades. Possible ways of treatment of patients with JNCL have been suggested. This article was reviewed by Konstantinos Lefkimmiatis, Eugene Koonin and Vladimir Poroikov. Show less