Mapping of Italian research excellence in Neurodegenerative Diseases

Pathogenesis of the CLN8 form of the late-infantile neuronal ceroid lipofuscinosis. The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative, lysosomal diseases with onset usually in childhood, being characterized by progressive visual loss, dementia, motor decline, therapy resistant epilepsy and early death. Our team has lately focused on the pathogenic mechanisms of the CLN8 variant form of the late-infantile NCLs (vLNCL), which is present in Finland, Turkey and Italy. The CLN8 gene encodes a transmembrane protein which is located mainly in the ER and partially in the ER-Golgi intermediate compartment of both neuronal and non-neuronal cells, and it is supposed to have a role in the ceramide synthesis. However, its exact function remains undiscovered. We have developed a protein-protein interaction study throughout the screening of a human brain cDNA library with split-ubiquitin membrane two-hybrid system in yeast, which is the only technology developed thus far that can work effectively as a in vivo screening system to find interactors of ER membrane proteins. This approach along with coimmuno-precipitation and -localization assays of transfected cells has envisaged for the first time four major protein interactors with the CLN8 protein. Through in vitro and in vivo studies, we are looking at the definition of the functional role of these interactions and particularly of the CLN8 interaction with two of the characterized proteins, which are known to have functions in synthesis and transport of lipids and are suggested to be involved in the amyothrophic lateral sclerosis. In an attempt to understand the mechanisms leading to neuronal cell death in the disease, we have been also using a spontaneous animal model of the CLN8/vNCL, the mnd mouse. We are currently investigating whether and how dysfunctions of ER/UPR system and autophagolysosomal pathway cooperate in the neurodegeneration of the retina and brain structures of the mnd model.