Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyos
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REVIEW
Open Access
Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum Robert J. Huber
Abstract The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, belong to a family of neurological disorders that cause blindness, seizures, loss of motor function and cognitive ability, and premature death. There are 13 different subtypes of NCL that are associated with mutations in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14). Similar clinical and pathological profiles of the different NCL subtypes suggest that common disease mechanisms may be involved. As a result, there have been many efforts to determine how NCL proteins are connected at the cellular level. A main driving force for NCL research has been the utilization of mammalian and non-mammalian cellular models to study the mechanisms underlying the disease. One non-mammalian model that has provided significant insight into NCL protein function is the social amoeba Dictyostelium discoideum. Accumulated data from Dictyostelium and mammalian cells show that NCL proteins display similar localizations, have common binding partners, and regulate the expression and activities of one another. In addition, genetic models of NCL display similar phenotypes. This review integrates findings from Dictyostelium and mammalian models of NCL to highlight our understanding of the molecular networking of NCL proteins. The goal here is to help set the stage for future work to reveal the cellular mechanisms underlying the NCLs. Keywords: Neuronal ceroid lipofuscinosis, Batten disease, Dictyostelium discoideum, Molecular networking, Neurodegeneration
Background Neuronal ceroid lipofuscinosis
The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, are devastating forms of neurodegeneration that affect the global population [1]. Mutations have been documented in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14), each of which causes a specific subtype of the disease (e.g., mutations in CLN3 cause CLN3 disease) [2, 3]. While the NCLs affect all ages and ethnicities, the disease is recognized as the most Correspondence: [email protected] Department of Biology, Trent University, 1600 West Bank Drive, Peterborough, Ontario K9L 0G2, Canada
common form of childhood neurodegeneration [1]. Clinical manifestations of the NCLs include seizures, vision loss, reduced mental capacity, decline in motor function, and a shortened lifespan [4]. At the cellular level, ceroid lipofuscin accumulates in neurons, as well as other cell types outside of the central nervous system, due to aberrant lysosomal function [5]. Unfortunately, there is currently no cure for the NCLs, in large part due to our poor understanding of the proteins associated with the disease. As a result, other than Brineura, which is an enzyme replacement therapy specific for only one subtype of the disease (CLN2 disease), there are currently no effective treatments to prevent or delay the NCLs [
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