Proteolytic processing of the neuronal ceroid lipofuscinosis related lysosomal protein CLN5

Silva, Bhagya De; Adams, Jessie; Lee, Stella Y.

doi:10.1016/j.yexcr.2015.08.021

Cited by 17 publications

(20 citation statements)

References 37 publications

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“…We found that preproCLN5 and proCLN5 are type II transmembrane domain proteins while mature CLN5 (mCLN5) is within the lumen of organelles and localizes to the lysosomal compartment. A recent study also demonstrated a further processing step as mCLN5 is processed in the lysosomal compartment as leupeptin blocked this final processing step [41]. Next to determine whether mCLN5 was soluble or membrane bound, we performed a Na2CO3 extraction and found that a significant portion of mCLN5 is soluble.…”

Section: Discussionmentioning

confidence: 92%

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein

Jules

Sauvageau

Dumaresq-Doiron

et al. 2017

Experimental Cell Research

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The Neuronal ceroid lipofuscinoses (NCLs) are a group of recessive disorders of childhood with overlapping symptoms including vision loss, ataxia, cognitive regression and premature death. 14 different genes have been linked to NCLs (CLN1-CLN14), but the functions of the proteins encoded by the majority of these genes have not been fully elucidated. Mutations in the CLN5 gene are responsible for the Finnish variant late-infantile form of NCL (Finnish vLINCL). CLN5 is translated as a 407 amino acid transmembrane domain containing protein that is heavily glycosylated, and subsequently cleaved into a mature soluble protein. Functionally, CLN5 is implicated in the recruitment of the retromer complex to endosomes, which is required to sort the lysosomal sorting receptors from endosomes to the trans-Golgi network. The mechanism that processes CLN5 into a mature soluble protein is currently not known. Herein, we demonstrate that CLN5 is initially translated as a type II transmembrane protein and subsequently cleaved by SPPL3, a member of the SPP/SPPL intramembrane protease family, into a mature soluble protein consisting of residues 93-407. The remaining N-terminal fragment is then cleaved by SPPL3 and SPPL2b and degraded in the proteasome. This work further characterizes the biology of CLN5 in the hopes of identifying a novel therapeutic strategy for affected children.

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Section: Discussionmentioning

confidence: 92%

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein

Jules

Sauvageau

Dumaresq-Doiron

et al. 2017

Experimental Cell Research

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“…While α-syn has been implicated in several cellular processes, including synaptic vesicle endocytosis 24 and exocytosis 25 , its exact function remains unclear. Despite being primarily associated with neurodegenerative disorders, both CLN5 and α-syn can be detected in a variety of tissues and cell types 26–31 . While this indicates more general roles of CLN5 and α-syn in non-neuronal tissues, there have been few studies performed to investigate these roles.…”

Section: Introductionmentioning

confidence: 99%

Autophagy–lysosome pathway alterations and alpha-synuclein up-regulation in the subtype of neuronal ceroid lipofuscinosis, CLN5 disease

Adams

Feuerborn

Molina

et al. 2019

Sci Rep

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Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders. CLN5 deficiency causes a subtype of NCL, referred to as CLN5 disease. CLN5 is a soluble lysosomal protein with an unclear function in the cell. Increased levels of the autophagy marker protein LC3-II have been reported in several subtypes of NCLs. In this report, we examine whether autophagy is altered in CLN5 disease. We found that the basal level of LC3-II was elevated in both CLN5 disease patient fibroblasts and CLN5-deficient HeLa cells. Further analysis using tandem fluorescent mRFP-GFP-LC3 showed the autophagy flux was increased. We found the alpha-synuclein (α-syn) gene SNCA was highly up-regulated in CLN5 disease patient fibroblasts. The aggregated form of α-syn is well known for its role in the pathogenicity of Parkinson’s disease. Higher α-syn protein levels confirmed the SNCA up-regulation in both patient cells and CLN5 knockdown HeLa cells. Furthermore, α-syn was localized to the vicinity of lysosomes in CLN5 deficient cells, indicating it may have a lysosome-related function. Intriguingly, knocking down SNCA reversed lysosomal perinuclear clustering caused by CLN5 deficiency. These results suggest α-syn may affect lysosomal clustering in non-neuronal cells, similar to its role in presynaptic vesicles in neurons.

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“…In the mouse brain, CLN5 is expressed in cortical neurons, hippocampal pyramidal neurons, hypothalamus, and cerebellum (93); the highest levels, however, have been detected in microglial cells (55,94). CLN5 protein undergoes posttranslational modifications that include glycosylation and cleavage (95,96). The depletion of CLN5 leads to lysosomal degradation of the retromer receptors sortilin and CI-M6PR (62).…”

Section: Neuronal Ceroid Lipofuscinosis and Retromermentioning

confidence: 99%

Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis

Qureshi

Baez

Reitz

2020

Molecular and Cellular Biology

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Neuronal Ceroid Lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early-life, Parkinson's Disease (PD) the most common neurodegenerative disorder of mid-life, while Alzheimer's disease (AD) is the most common neurodegenerative disorders of late-life. While phenotypically distinct, recent studies suggest that they might share a common biological pathway—retromer-dependent endosomal trafficking. ‘Retromer’ is a multi-modular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL's causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer, and others causing endolysosomal dysfunction. AD has over twenty-five causative genes/risk factors with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL to retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD and discuss how NCL, AD and PD converge onto a shared molecular pathway. We will also discuss this pathway's role in microglia and neurons - cell populations critical to proper brain homeostasis, and dysfunction of which plays a key role in neurodegeneration.

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Proteolytic processing of the neuronal ceroid lipofuscinosis related lysosomal protein CLN5

Cited by 17 publications

References 37 publications

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein

Autophagy–lysosome pathway alterations and alpha-synuclein up-regulation in the subtype of neuronal ceroid lipofuscinosis, CLN5 disease

Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis

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