Neuronal Ceroid Lipofuscinosis: A Common Pathway?

Abstract

ABSTRACT:The neuronal ceroid lipofuscinoses are pediatric neurodegenerative diseases with common clinical features. Of the nine clinical variants (CLN1-CLN9), six have been genetically identified. Most variants manifest cell death and dysregulated sphingolipid metabolism, suggesting the proteins defective in these disorders may interact along one pathway. NCL patientderived cell lines exhibit cell growth and apoptotic defects that reverse following transfection with the wild-type gene. The membrane-bound proteins CLN3, CLN6, and CLN8 complement each other, as do CLN1 and CLN2 proteins, with respect to growth and apoptosis. The CLN2 protein also corrects growth and apoptosis in CLN3-, CLN6-, and CLN8-deficient cell lines. Neither CLN1-deficient nor CLN2-deficient growth defects are corrected by CLN3, CLN6, and CLN8 proteins. CLN2, CLN3, CLN6, and CLN8 proteins co-immunoprecipitate and co-localize to early and/or recycling endosomes and lipid rafts. Additionally, CLN2p and CLN1p co-immunoprecipitate. The work presented supports interactions between NCL proteins occurring at multiple points along one pathway. (Pediatr Res 61: 146-152, 2007)

2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy

“…Specifically, we used fibroblasts derived from a patient with LINCL, a disease caused by deficiency of tripeptidyl peptidase (TPP1) activity. Previous studies showed that cells derived from patients with LINCL or other NCLs have an increased tendency to undergo apoptosis (42). Thus, apoptosis-sensitive LINCL fibroblasts were selected for this study to investigate whether HP␤CD treatment affects autophagic clearance of ceroid lipofuscin and whether HP␤CD-induced modulation of autophagy also activates cell death mechanisms (see below).…”

“…To investigate whether administration of HP␤CD increases apoptosis under the conditions used in this study, we used LINCL fibroblasts, which present higher propensity to undergo apoptosis compared with wild type fibroblast (42). We monitored induction of early and late apoptosis by measuring membrane rearrangement, characteristic of early apoptosis (annexin V binding), and membrane fragmentation, characteristic of late apoptosis (propidium iodide binding), using the Cyto-GLO TM annexin V-FITC apoptosis detection kit as previously described (47).…”

“…The hallmark of NCLs is the aberrant intracellular accumulation of autofluorescent ceroid lipopigments due to mutations in genes encoding proteins involved in lysosomal biogenesis and function (41). NCL patient-derived cell lines exhibit slowed growth and increased propensity to undergo apoptosis (42). Interestingly, TFEB activation was shown to lower the accumulation of ceroid lipopigments in fibroblasts derived from a patient with juvenile NCL (43), suggesting a potential role of TFEB as a therapeutic target for the treatment of NCLs.…”

Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis

“…There is growing experimental evidence relating the function of different NCL genes and pointing to possible shared biochemical pathways (Vesa et al, 2002;Siintola et al, 2006). It is tempting to speculate that the MFSD8/CLN7 gene product might act as an additional member in a common biochemical cascade, with protein dysfunction leading to neurodegeneration (Holopainen et al, 2000;Persaud-Sawin et al 2007). Further knowledge of these interactions will be important for development of therapeutic strategies (Mole et al, 2005).…”

CLN3p Impacts Galactosylceramide Transport, Raft Morphology, and Lipid Content

“…The work uncovers a novel mechanism for neurodegeneration. NCL complementation groups regarding growth/ apoptosis, coimmunoprecipitation of NCL proteins and colocalization to subcellular compartments are described (38). Binding of CLN1/CLN2/CLN6/CLN8p to sulfatide/GalCer/LPA/ ceramide, and raft sphingolipid content/morphology from cells deficient in these proteins suggest lipid-binding/trafficking defects and raft sphingolipid content/morphology are common themes for NCL.…”