Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice

Kollmann, Katrin; Damme, Markus; Markmann, Sandra; Morelle, Willy; Schweizer, Michaela; Hermans‐Borgmeyer, Irm; Rochert, A K; Pohl, Sandra; Lübke, Torben; Jc, Michalski; Käkelä, Reijo; Walkley, Steven U.; Braulke, Thomas

doi:10.1093/brain/aws209

Cited by 73 publications

(109 citation statements)

References 60 publications

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“…31 The presence of LAMP-1 and -2 in their limiting membranes further defines them as autolysosomes, which is in agreement with observations in MLII mouse models that show the presence of autolysosomes in exocrine secretory cells and compartments with similar morphology in various cell types. [32][33][34] In summary, the characterization of the endo-lysosomal system in MLII B cells shows that these cells have decreased numbers of type V late endosomes and lysosomes but instead accumulate inclusion bodies/autolyosomes with undigested material.…”

Section: B Cells Accumulate Inclusion Bodiesmentioning

confidence: 94%

TGN exit of the cation-independent mannose 6-phosphate receptor does not require acid hydrolase binding

Meel

Klumperman

2014

Cellular Logistics

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The cation-independent mannose 6-phosphate (Man-6-P) receptor (CI-MPR) binds newly synthesized, Man-6-Pcontaining lysosomal acid hydrolases in the trans-Golgi network (TGN) for clathrin-mediated transport to endosomes. It has remained unresolved, however, whether acid hydrolase binding is required for exit of the CI-MPR from the TGN. To address this question we used a B cell line derived from a Mucolipidosis type II (MLII)/I-cell disease patient. In MLII patients, acid hydrolases do not acquire the Man-6-P recognition marker and as a consequence do not bind to the CI-MPR. This causes secretion of the majority of the acid hydrolases and a decreased lysosomal activity resulting in typical inclusion bodies. In agreement herewith, ultrastructural analysis of the MLII patient derived B cells showed numerous inclusion bodies with undigested material, which we defined as autolysosomes. By quantitative immuno-electron microscopy we then studied the distribution of the CI-MPR in these cells. We found that the level of co-localization of TGN-localized CI-MPR and clathrin was similar in MLII and control B cells. Moreover, the CI-MPR was readily found in endosomes of MLII cells and the TGN-to-early endosome ratio of CI-MPR labeling was unaltered. These data show that there is no block in TGN exit of the CI-MPR in the absence of Man-6-P-modified acid hydrolases. Notably, late endosomes and inclusion bodies in MLII B cells contained increased levels of the CI-MPR, which likely reflects the reduced degradative capacity of these compartments.

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Section: B Cells Accumulate Inclusion Bodiesmentioning

confidence: 94%

TGN exit of the cation-independent mannose 6-phosphate receptor does not require acid hydrolase binding

Meel

Klumperman

2014

Cellular Logistics

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“…Interestingly, apart from the reasonably well-characterized culprits, such as psychosine, increased amounts of ROS and susceptibility to LMP seems to be a feature of an increasing number of LSDs ( 57,(66)(67)(68)(69). As LMP is a well-described initiator of cell death programs, modifying this phenotype presents an attractive area for therapeutic intervention, not only in LSDs but also in other diseases in which this deleterious process is involved, such as cancer and pancreatitis ( 13,58,70 ).…”

Section: Proteostasismentioning

confidence: 99%

“…The lysosome contains a high content of hydrolytic enzymes, and loss of lysosomal integrity is potentially lethal to the cell, as evidenced by the involvement of LMP in a number of cell death cascades and pathologies, including a number of the LSDs ( 13,57,(66)(67)(68)(69)71 ).…”

Section: Lmpmentioning

confidence: 99%

“…Also, generation of ceramide alters the biophysical properties of cellular membranes ( 87 ). The ultimate outcome of changes in lysosomal membrane lipid stoichiometry is thus hard to predict, but studies have shown that loss of lysosomal integrity is a feature across the various classes of LSDs, as diseases as diverse as Niemann-Pick disease types A and B, NiemannPick disease type C, mucopolysaccharidosis type I, mucolipidosis type II, and late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) all have been reported to be susceptible to LMP ( 57,(66)(67)(68)(69).…”

Section: +mentioning

confidence: 99%

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Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Ingemann

Kirkegaard

2014

Journal of Lipid Research

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The lysosomal storage diseases (LSDs) describe a heterogenous family of rare inherited diseases caused by mutations in lysosomal proteins and are characterized by accumulation of macromolecules or monomeric compounds inside organelles of the endo-lysosomal system ( 1-3 ). The LSDs present complex disease phenotypes with the mechanisms leading to pathology being poorly understood, as the disease and extent of pathology seem to depend on the spatiotemporal accumulation of substrates which have a variety of downstream effects depending on their cellular and physiological context ( Table 1 ). It is thus diffi cult to generalize for the LSDs, but as the origin of the diseases in all cases is a genetic lesion, which most often causes a misfolded dysfunctional protein, the cellular processes and responses related to misfolded proteins have to be considered as an integral part of the etiology of any of the diseases. Thus, the shared mechanistic principle of disturbed protein homeostasis and the fact that many LSDs also show an overlap of potentially toxic storage compounds might explain why the LSDs, despite their various monogenetic origins, share a number of cellular and clinical manifestations including perturbed lysosomal traffi cking and autophagy, increased oxidative stress, impaired calcium homeostasis, loss of lysosomal stability, increased Abstract Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defi ned loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a p...

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“…Mouse embryonic fi broblasts (MEFs) of WT and MLII "knockin" mice were prepared as previously described ( 18 ). Human fibroblasts were obtained from skin biopsies with informed consent of two controls and three NPC1 patients carrying the following mutations encoded by the NPC1 gene: Patient 1 (P1) was heterozygous for p.G910S and p.G1034R; patient 2 (P2) and patient 3 (P3) were homozygous for p.S940L and p.I1095del, respectively.…”

Section: Cell Culture and Cdna Transfectionmentioning

confidence: 99%

Site-1 protease-activated formation of lysosomal targeting motifs is independent of the lipogenic transcription control

Klünder

Heeren

Markmann

et al. 2015

Journal of Lipid Research

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endocytosis, autophagy, and phagocytosis through the concerted action of more than 50 acid hydrolases ( 1 ). To maintain their function, lysosomes require a continuous replenishment of newly synthesized components transported from the endoplasmic reticulum (ER) via the Golgi apparatus to the endosomal/lysosomal compartment. The effi cient transport of soluble lysosomal enzymes to lysosomes requires mannose 6-phosphate (M6P) residues on their N -linked glycans, which serve as recognition markers for M6P-specifi c receptors (MPRs) ( 2 ). The formation of M6P residues is catalyzed by two enzymes, the N -acetylglucosamine-1-phosphotransferase (termed "GlcNAc-1-phosphotransferase") and the GlcNAc-1-phosphodiester ␣ -N -acetylglucosaminidase (termed "uncovering enzyme") localized in the cis -Golgi apparatus and trans -Golgi network, respectively ( 3 ).The GlcNAc-1-phosphotransferase is a heterohexameric complex of three subunits ( ␣ 2 ␤ 2 ␥ 2 ), which are encoded by two genes ( 4-6 ). The ␣ -and ␤ -subunits of the GlcNAc-1-phosphotransferase are synthesized in the ER as a single, highly N -glycosylated, 190 kDa, type III membrane protein ( 6 ). For the transport to the Golgi apparatus, combinatorial dileucine and dibasic sorting motifs in the N-and C-terminal cytosolic domains, respectively, are required ( 7 ). Upon arrival in the cis -Golgi compartment, the ␣ / ␤ -subunit precursor is proteolytically cleaved by the site-1 protease (S1P) into mature ␣ -and ␤ -subunits ( 8 ), which are prerequisite for the enzymatic activity of the GlcNAc-1-phosphotransferase complex ( 9 ).Abstract Site-1 protease (S1P) cleaves membrane-bound lipogenic sterol regulatory element-binding proteins (SREBPs) and the ␣ / ␤ -subunit precursor protein of the N -acetylglucosamine-1-phosphotransferase forming mannose 6-phosphate (M6P) targeting markers on lysosomal enzymes. The translocation of SREBPs from the endoplasmic reticulum (ER) to the Golgi-resident S1P depends on the intracellular sterol content, but it is unknown whether the ER exit of the ␣ / ␤ -subunit precursor is regulated. Here, we investigated the effect of cholesterol depletion (atorvastatin treatment) and elevation (LDL overload) on ER-Golgi transport, S1P-mediated cleavage of the ␣ / ␤ -subunit precursor, and the subsequent targeting of lysosomal enzymes along the biosynthetic and endocytic pathway to lysosomes. The data showed that the proteolytic cleavage of the ␣ / ␤ -subunit precursor into mature and enzymatically active subunits does not depend on the cholesterol content. In either treatment, lysosomal enzymes are normally decorated with M6P residues, allowing the proper sorting to lysosomes. In addition, we found that, in fi broblasts of mucolipidosis type II mice and Niemann-Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the ␣ / ␤ -subunit precursor was not impaired. We conclude that S1P substrate-dependent regulatory mechanisms for lipid synthesis and biogenesis of lysosomes are different. T.B., and S.P.) and GR...

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Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice

Cited by 73 publications

References 60 publications

TGN exit of the cation-independent mannose 6-phosphate receptor does not require acid hydrolase binding

TGN exit of the cation-independent mannose 6-phosphate receptor does not require acid hydrolase binding

Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Site-1 protease-activated formation of lysosomal targeting motifs is independent of the lipogenic transcription control

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