Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

Lebrun, AH; Storch, Stephan; Kyttällä, A; Mole, SE; Kohlschütter, Alfried; Kruse, Brigitte; Ullrich, Kurt; Braulke, Thomas; Schulz, Ava

doi:10.1055/s-0029-1215800

Cited by 11 publications

(18 citation statements)

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“…These results are in line with the observation that CLN5 mutants contain complex sugars, suggesting that they reach the Golgi but are transported back to the ER [Schmiedt et al., ]. Two other mutations in the AH (p.Leu358Alafs*4 and p.Trp379Cys) have been reported to lead to the redistribution of CLN5 to the ER [Lebrun et al., ]. To better understand the role of the AH in CLN5 function, it would be interesting to determine whether these mutations, as well as others identified in the AH [Mole et al., ], alter the membrane anchoring, secretion, and stability of CLN5.…”

Section: Discussionsupporting

confidence: 73%

“…However, it has also been described as a soluble protein and has been detected in culture media [Holmberg et al., ; Sleat et al., ]. To date, none of the CLN5 disease‐causing mutations studied have been shown to have an effect on CLN5 synthesis and maturation, but they are known to affect the lysosomal targeting of CLN5 [Isosomppi et al., ; Lebrun et al., ; Schmiedt et al., ; Vesa et al., ].…”

Section: Introductionmentioning

confidence: 99%

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Topology and Membrane Anchoring of the Lysosomal Storage Disease-Related Protein CLN5

2013

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One late infantile variant of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL) is caused by a mutation in the CLN5 gene. CLN5 encodes a lysosomal glycoprotein whose structure and function have not yet been clearly defined. In the present study, we used epitope-tagged CLN5 to determine the topology and solubility of the CLN5 protein. Our results indicated that CLN5 is synthesized as a type II transmembrane (TM) glycoprotein with a cytoplasmic N-terminus, one TM segment, and a large luminal C-terminal domain containing an amphipathic helix (AH). The cytoplasmic and TM domains were rapidly removed following signal-peptide cleavage, and the resulting mature CLN5 was tightly associated with the lumen of the membrane through the AH. CLN5 pathological mutants deprived of AH lose their membrane association, are retained in the endoplasmic reticulum, and are rapidly degraded by the proteasomal machinery. We experimentally define the topology of CLN5 and demonstrate the existence of an AH that anchors the protein to the membrane. Our work sheds light on the basic properties of CLN5 required to better understand its biological functions and involvement in NCL pathogenesis.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Topology and Membrane Anchoring of the Lysosomal Storage Disease-Related Protein CLN5

2013

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“…Recently, a 52-kDa polypeptide was detected for overexpressed CLN5 in BHK and COS-7 cells by using a different antibody. Furthermore, the study only reported high mannose-type sugars for CLN5 [Lebrun et al, 2009]. In this study, using stably transfected CLN5-SH-SY5Y cells and the novel C-terminal antibody, we were able to detect the presence of both 60-and 50-kDa CLN5 polypeptides.…”

Section: Discussionmentioning

confidence: 72%

“…Mutations in the CLN5 gene have been reported to prevent trafficking of CLN5 to the level of ER [Lebrun et al, 2009] and Golgi] Isosomppi et al, 2002], but also not dramatically affect trafficking to the lysosomes . However, some of the previous data is conflicting Vesa et al, 2002], possibly as a result of the usage of different cell lines in the overexpression studies (COS, BHK, HeLa).…”

Section: Discussionmentioning

confidence: 99%

The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations

et al. 2010

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Neuronal ceroid lipofuscinoses (NCLs) represent a group of children's inherited neurodegenerative disorders caused by mutations in at least eight different genes. Mutations in the CLN5 gene result in the Finnish variant late infantile NCL characterized by gradual loss of vision, epileptic seizures, and mental deterioration. The CLN5 gene encodes a lysosomal glycoprotein of unidentified function. In this study, we have used both transient and stable expression systems for the characterization of CLN5, focusing on the localization, processing, and intracellular trafficking. We show that CLN5 is proteolytically cleaved, and that the mature polypeptide is transported to the lysosomes. Our data provide the first evidence that soluble CLN5 protein can also undergo mannose-6-phosphate receptor-independent trafficking to the lysosomes. We studied the localization and maturation of the CLN5 carrying the previously uncharacterized vLINCL disease causing mutations in HeLa cells. All analyzed disease mutations disturb the lysosomal trafficking of the mutated CLN5 proteins. The level of lysosomal targeting does not correlate, however, to disease onset, indicating that CLN5 may also function outside lysosomes. This study furthers our understanding of the basic properties of the CLN5 protein, necessary for the characterization of the consequences of disease mutations and for the planning of future therapies for vLINCL.

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“…The variety of genotype-phenotype combinations means a major challenge of NCL therapies so that the most appropriate and effective therapy can be directed for each NCL type. A new diagnostic algorithm consensus was reached during theAfghanistan-Pakistan [67], and Argentina [27,28]. The basic defect concerns a soluble protein, apparently localized in lysosomes, whose function may be linked to that of other NCL proteins.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

Kohan¹,

Cismondi²,

Oller-Ramírez³

et al. 2011

CPB

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The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

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Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

Cited by 11 publications

References 0 publications

Topology and Membrane Anchoring of the Lysosomal Storage Disease-Related Protein CLN5

Topology and Membrane Anchoring of the Lysosomal Storage Disease-Related Protein CLN5

The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

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