Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

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.

Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease

“…In addition, Dictyostelium is the only lower eukaryotic model system that contains homologs of human tripeptidyl peptidase (TPP1, also known as CLN2) and CLN5 (Huber, 2016). Homologs of human TPP1/CLN2, CLN3, CLN5, and major facilitator superfamily domain-containing protein 8 (MFSD8, also known as CLN7) have been previously studied in Dictyostelium, which has contributed to our understanding of the localizations and functions of these proteins in human cells (Huber et al, 2014(Huber et al, , 2017(Huber et al, , 2020bPhillips and Gomer, 2015;Huber, 2017Huber, , 2020Stumpf et al, 2017;Mathavarajah, 2018a,b, 2019; Abbreviations: cAMP, cyclic adenosine monophosphate; CadA, calciumdependent cell adhesion molecule A; CLN, ceroid lipofuscinosis neuronal; CtnA, countin; CtsD, cathepsin D; FM, minimal media; HEXA, hexosaminidase A; HL5, nutrient-rich media; NagA, N-acetylglucosaminidase A; NCL, neuronal ceroid lipofuscinosis; NGT, N-acetylglucosamine thiazoline; TPP1, tripeptidyl peptidase 1; WT, wild type. Mathavarajah et al, 2018;Smith et al, 2019).…”

Urine proteomics analysis of patients with neuronal ceroid lipofuscinoses

“…Often researchers turn to animal or cell models to address this. One such model is the slime mold Dictyostelium , which has revealed how secretion is impaired in NCL ( Huber et al., 2014 ; Huber, 2020 ). Proteins observed to be altered in Dictyostelium were also observed to be altered in human patient tissues ( Sleat et al., 2017 ).…”

The converging roles of Batten disease proteins in neurodegeneration and cancer

“…Despite our analyses in Figures 1 , 2 , and 3 showing genetic perturbations in CLN6 , MFSD8 , CLN8 , and KCTD7 across various tumors and their influence on patient prognosis with respect to brain cancer, the specific roles of these genes in cancer-related processes has yet to be explored in detail. However, the pathways regulated by these genes also encompass pathways that are shared between cancer and the NCLs (e.g., ceramide pathway and protein homeostasis) ( Cárcel-Trullols et al., 2015 ; Huber, 2020 ; Persaud-Sawin et al., 2007 ). These findings indicate their possible involvement in oncogenesis and should be investigated further.…”

“…The NCL family of proteins comprises soluble lysosomal enzymes (CLN1/PPT1, palmitoyl protein thioesterase 1; CLN2/TPP1, tripeptidyl peptidase 1; CLN5, ceroid lipofuscinosis neuronal 5; CLN10/CTSD, cathepsin D; CLN13/CTSF, cathepsin F), lysosomal transmembrane proteins (CLN3, ceroid lipofuscinosis neuronal 3; CLN7/MFSD8, major facilitator superfamily domain-containing 8; CLN12/ATP13A2, ATPase 13A2), proteins associated with vesicular membranes (CLN4/DNAJC5, DnaJ heat shock protein family member C5; CLN14/KCTD7, potassium channel tetramerization domain-containing 7), membrane proteins that reside in the endoplasmic reticulum (ER) (CLN6, ceroid lipofuscinosis neuronal 6; CLN8, ceroid lipofuscinosis neuronal 8) and a secreted glycoprotein (CLN11/PGRN, progranulin) ( Cárcel-Trullols et al., 2015 ). Despite the molecular genetic heterogeneity of these proteins, research in non-mammalian and mammalian models suggests that the NCL proteins may participate in shared or converging pathways ( Huber, 2020 ; Persaud-Sawin et al., 2007 ). However, the precise functions of NCL proteins, their interactions with one another, and the underlying mechanisms that lead to NCL pathology are poorly understood, which has severely hindered therapy development.…”