The neuronal ceroid lipofuscinoses: Opportunities from model systems

Abstract

The neuronal ceroid lipofuscinoses are a group of severe and progressive neurodegenerative disorders, generally with childhood onset. Despite the fact that these diseases remain fatal, significant breakthroughs have been made in our understanding of the genetics that underpin these conditions. This understanding has allowed the development of a broad range of models to study disease processes, and to develop new therapeutic approaches. Such models have contributed significantly to our knowledge of these conditions. In this review we will focus on the advantages of each individual model, describe some of the contributions the models have made to our understanding of the broader disease biology and highlight new techniques and approaches relevant to the study and potential treatment of the neuronal ceroid lipofuscinoses. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

“…In addition to affecting people, NCL-like disorders have been reported to occur naturally in a number of other mammalian species including dogs, cats, cattle, horses, sheep, mice, and monkeys, as well as in some non-mammalian species (Bildfell et al, 1995; Bond et al, 2013; Broom et al, 1998; Cesta et al, 2006; Chalkley et al, 2014; Evans et al, 2012; Fiske and Storts, 1988; Frugier et al, 2008; Gao et al, 2002; Green and Little, 1974; Hafner et al, 2005; Houweling et al, 2006; Jasty et al, 1984; Jolly et al, 1994a; Jolly and Palmer, 1995; Kay Read and Bridges, 1969; Nakayama et al, 1993; Nibe et al, 2011; Ranta et al, 1999; Reece and MacWhirter, 1988; Tammen et al, 2006; Tyynela et al, 2000; Url et al, 2001; Weissenbock and Rossel, 1997; Wheeler et al, 2002; Woods et al, 1993). Mouse, pig, fish, and insect models of the NCLs have also been created through genetic engineering (Bond et al, 2013; Bouchelion et al, 2014; Faller et al, 2015; Miller et al, 2015; Schultheis et al, 2013). Although many naturally occurring progressive neurological disorders in dogs have been reported as NCLs, for the purposes of this review only those disorders in which the disease has been associated with mutations in the canine ortholog of one of the 13 known human NCL genes will be considered to be confirmed cases of NCL.…”

Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs)

“…51,54 Of particular significance are the PPT1 knockout mice models mimicking the CLN1 disease state, and the Cln3 Δex1–6 mimicking the CLN3 disease state, as the majority of small molecule therapeutic invetsigation for NCLs are performed using these models. Other mice models for CLN3 disease such as Cln3 Δex7/8 knockout, Cln3 Δex7/8 knock-in, and Cln3 LacZ β-galactosidase have also been developed.…”

Using the social amoeba Dictyostelium to study the functions of proteins linked to neuronal ceroid lipofuscinosis

“…Homologs of NCL proteins have been identified and studied in several model organisms and this work has significantly enhanced our understanding of the localization and functions of NCL proteins in humans [26–28]. The Dictyostelium genome contains homologs of 11 of the 13 known NCL genes, but does not contain homologs of CLN6 or CLN8 (Table 2).…”

“…Of all the NCL proteins, these are the only ER-resident membrane proteins [29, 30]. By comparison, Dictyostelium contains more homologs of NCL proteins than other model organisms including budding and fission yeast, the nematode Caenorhabditis elegans , and the fruit fly Drosophila melanogaster , but fewer than zebrafish ( Danio rerio ) [26–28] (Table 3). While the functions of some of the homologs in Dictyostelium have been investigated using gene-deficiency models, knockout mutants for several of the genes have yet to be generated (e.g., ppt1/cln1 , ddj1/cln4 , cln5 , mfsd8/cln7 , grn/cln11 , cprA/cln13 ).…”

“…The information contained within this table is described in detail elsewhere [26–28]. The presence and absence of homologs in each organism was confirmed with NCBI BLASTp [a], WormBase BLASTp [b], and FlyBase BLASTp [c]…”