Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material

Xu, Su; Sleat, David E.; Jadot, Michel; Lobel, Peter

doi:10.1042/bj20100128

Cited by 11 publications

(9 citation statements)

References 43 publications

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“…PSAP is a known component of the storage material in CLN1 14 and is highly elevated compared with control samples when quantified by MS (Figure 6B). Although not a component of storage material but instead reflecting glial activation, GFAP is elevated in CLN2 43 and other NCLs, and, consistent with this, quantitative MS analysis indicates that levels in the NCL samples are elevated compared with controls. Taken together, the strong correlation between quantitative MS and functional assay data and the detection of specific changes in brain that are predicted from previous studies provide strong validation of the MS-based approach and provide confidence in the interpretation of previously unrecognized protein expression changes in NCL samples.…”

Section: Validation Of Quantitative Proteomic Analysis Of Brain Extra...supporting

confidence: 64%

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Sleat

Tannous²,

Sohár³

et al. 2017

J. Proteome Res.

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Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. Whereas clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3 protein (CLN3 disease). Proteomic and biochemical methods were used to analyze lysosomal proteins, and, in general, we find that changes in protein expression compared with control were most similar between CLN2 disease and CLN3 disease. This is consistent with previous observations of biochemical similarities between these diseases. We also conducted unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative mass spectrometry. Significant alterations in protein expression were identified in each NCL, including reduced STXBP1 in CLN1 disease brain. Given the confounding variable of post-mortem changes, additional validation is required, but this study provides a useful starting set of candidate NCL biomarkers for further evaluation.

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Section: Validation Of Quantitative Proteomic Analysis Of Brain Extra...supporting

confidence: 64%

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Sleat

Tannous²,

Sohár³

et al. 2017

J. Proteome Res.

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“…Altered expression levels of Glial fibrillary acidic protein (GFAP) were found in the MPS IIIB mouse brain. This finding is consistent with previous studies that highlighted a deregulation of GFAP in several lysosomal storage diseases, including MPS IIIB [18,[87][88][89][90][91][92][93][94][95]. The protein GFAP is a molecular marker of astrocytes that are fundamental for the neuronal microenvironment in order to control the metabolism of glucose, neurotransmitters re-uptake, and the formation and maturation of the synapses.…”

Section: Other Proteinssupporting

confidence: 92%

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

et al. 2020

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Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363.

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“…Furthermore, a biochemical study analyzing storage isolated from Cln2 Ϫ/Ϫ mice identified material associated with both a lysosomal subcellular fraction and an insoluble protein fraction (Xu et al, 2010). Notably, p62 was found to be the predominant component associated with the insoluble fractions.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal Membrane Permeability Stimulates Protein Aggregate Formation in Neurons of a Lysosomal Disease

Micsenyi

Sikora

Stephney

et al. 2013

Journal of Neuroscience

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Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2 Ϫ/Ϫ mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin-proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra-lysosomal aggregates in Cln2 Ϫ/Ϫ neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation.

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Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material

Cited by 11 publications

References 43 publications

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain

Lysosomal Membrane Permeability Stimulates Protein Aggregate Formation in Neurons of a Lysosomal Disease

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