<scp>CLN</scp>5 and <scp>CLN</scp>8 protein association with ceramide synthase: <scp>B</scp>iochemical and proteomic approaches

Haddad, Saria El; Khoury, Marwan; Daoud, Mohammad Mahdi; Kantar, Rami S.; Harati, Hayat; Mousallem, Talal; Álzate, Óscar; Meyer, Brian F.; Boustany, Rose-Mary

doi:10.1002/elps.201200472

Cited by 53 publications

(40 citation statements)

References 44 publications

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“…However, this finding is inconsistent with the soluble lysosomal protein properties of CLN5. CLN5 has also been suggested to function as a regulator of dihydroceramide synthase [14], [15].…”

Section: Introductionmentioning

confidence: 99%

The Role of N-Glycosylation in Folding, Trafficking, and Functionality of Lysosomal Protein CLN5

et al. 2013

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CLN5 is a soluble lysosomal protein with unknown function. Mutations in CLN5 lead to neuronal ceroid lipofuscinosis, a group of inherited neurodegenerative disorders that mainly affect children. CLN5 has eight potential N-glycosylation sites based on the Asn-X-Thr/Ser consensus sequence. Through site-directed mutagenesis of individual asparagine residues to glutamine on each of the N-glycosylation consensus sites, we showed that all eight putative N-glycosylation sites are utilized in vivo. Additionally, localization studies showed that the lack of N-glycosylation on certain sites (N179, N252, N304, or N320) caused CLN5 retention in the endoplasmic reticulum, indicating that glycosylation is important for protein folding. Interestingly, one particular mutant, N401Q, is mislocalized to the Golgi, suggesting that N401 is not important for protein folding but essential for CLN5 trafficking to the lysosome. Finally, we analyzed several patient mutations in which N-glycosylation is affected. The N192S patient mutant is localized to the lysosome, indicating that this mutant has a functional defect in the lysosome. Our results suggest that there are functional differences in various N-glycosylation sites of CLN5 which affect folding, trafficking, and lysosomal function of CLN5.

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Section: Introductionmentioning

confidence: 99%

The Role of N-Glycosylation in Folding, Trafficking, and Functionality of Lysosomal Protein CLN5

et al. 2013

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“…The exact number of genes that can cause NCL remains uncertain. At least one family thought to represent CLN9 , and associated with disease of juvenile-onset, and specific cell characteristics, is now reclassified as a CLN5 variant [29]. However, the genetic basis in at least one other similar family has yet to be clarified [30].…”

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confidence: 99%

Genetics of the neuronal ceroid lipofuscinoses (Batten disease)

Mole

Cotman

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

274

300

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The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults, and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomal protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.

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“…ATP13A2 is a lysosomal transport protein that helps maintain optimal pH in lysosomes [46], and ceramide is metabolized in lysosomes [77]. The apoptosis that appears to cause NCLs is associated with increased levels of ceramide [78, 79], which have also been linked to α -synuclein deposition, which may contribute to PD pathogenesis [80]. It may be that ATP13A2 helps regulate ceramide metabolism, such that significant changes in ATP13A2 activity may contribute to the pathogenesis of both PD and NCLs.…”

Section: Atp13a2 Mutations: a Link Between Parkinsonism And Nclsmentioning

confidence: 99%

Mutations in theATP13A2Gene and Parkinsonism: A Preliminary Review

Yang

2014

BioMed Research International

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Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.

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CLN5 and CLN8 protein association with ceramide synthase: Biochemical and proteomic approaches

Cited by 53 publications

References 44 publications

The Role of N-Glycosylation in Folding, Trafficking, and Functionality of Lysosomal Protein CLN5

The Role of N-Glycosylation in Folding, Trafficking, and Functionality of Lysosomal Protein CLN5

Genetics of the neuronal ceroid lipofuscinoses (Batten disease)

Mutations in theATP13A2Gene and Parkinsonism: A Preliminary Review

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