Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

Nelvagal, Hemanth R.; Hurtado, Maica Llavero; Eaton, Samantha L.; Kline, Ronald A.; Lamont, Douglas J.; Sands, Mark S.; Wishart, Thomas M.; Cooper, Jonathan D.

doi:10.1038/s41598-020-72075-7

Cited by 11 publications

(13 citation statements)

References 66 publications

(148 reference statements)

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“…Nonetheless, several proteins altered in our transcriptomic analysis (LYZ2, TGM1, GPNMB, C4B, SERPINA3N, GFAP and C1QC) were confirmed to be increased in the proteomics analysis of CLN2 and were related to microglial and astrocytic function [ 32 ]. Interestingly, proteomic profiling of spinal cord in CLN1 disease (Ppt1 −/− model) identified canonical pathways consistent with the ones identified in this study for the Tpp1 −/− brains [ 96 ]; as well, notable regional differences were found in this study.…”

Section: Discussionsupporting

confidence: 85%

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

Domowicz

Chan

Claudio-Vázquez

et al. 2021

J Neuroinflammation

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Background Neuronal ceroid lipofuscinoses, (NCLs or Batten disease) are a group of inherited, early onset, fatal neurodegenerative diseases associated with mutations in 13 genes. All forms of the disease are characterized by lysosomal accumulation of fluorescent storage material, as well as profound neurodegeneration, but the relationship of the various genes’ function to a single biological process is not obvious. In this study, we used a well-characterized mouse model of classical late infantile NCL (cLINCL) in which the tripeptidyl peptidase 1 (Tpp1) gene is disrupted by gene targeting, resulting in loss of detectable TPP1 activity and leading to progressive neurological phenotypes including ataxia, increased motor deficiency, and early death. Methods In order to identify genes and pathways that may contribute to progression of the neurodegenerative process, we analyzed forebrain/midbrain and cerebellar transcriptional differences at 1, 2, 3 and 4 months of age in control and TPP1-deficient mice by global RNA-sequencing. Results Progressive neurodegenerative inflammatory responses involving microglia, astrocytes and endothelial cells were observed, accompanied by activation of leukocyte extravasation signals and upregulation of nitric oxide production and reactive oxygen species. Several astrocytic (i.e., Gfap, C4b, Osmr, Serpina3n) and microglial (i.e., Ctss, Itgb2, Itgax, Lyz2) genes were identified as strong markers for assessing disease progression as they showed increased levels of expression in vivo over time. Furthermore, transient increased expression of choroid plexus genes was observed at 2 months in the lateral and fourth ventricle, highlighting an early role for the choroid plexus and cerebrospinal fluid in the disease pathology. Based on these gene expression changes, we concluded that neuroinflammation starts, for the most part, after 2 months in the Tpp1−/− brain and that activation of microglia and astrocytes occur more rapidly in cerebellum than in the rest of the brain; confirming increased severity of inflammation in this region. Conclusions These findings have led to a better understanding of cLINCL pathological onset and progression, which may aid in development of future therapeutic treatments for this disease.

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Section: Discussionsupporting

confidence: 85%

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

Domowicz

Chan

Claudio-Vázquez

et al. 2021

J Neuroinflammation

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“…The secretion of cytokines and chemokines is of paramount importance for both astrocytes and microglia to exert pro- and anti-inflammatory effects on the process of neurodegeneration ( 93 ). The progressive elevation of multiple cytokines and chemokines has been confirmed by whole transcriptomics and/or proteomics in the forebrains and cerebella of Tpp 1 −/− mice ( 75 , 90 ) and forebrains and spinal cords of Ppt 1 −/− mice ( 68 , 94 , 95 ). Such evidence for the region- and subtype-specific nature of neuroinflammatory changes in CLN1 and CLN2 diseases correlates with the previously shown region- and subtype-specific immunoreactivity of astrogliosis and microglial activation markers.…”

Section: Glial Dysfunction In the Nclsmentioning

confidence: 85%

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

et al. 2022

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While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research.

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“…Moreover, the data obtained from the proteomic analysis can be used for dissecting the molecular targets and signaling pathways of a specific pathology. Previously, mass spectrometry (MS)-based proteomics protocols were applied to the investigation of different LSDs models such as CLN1 disease [12], Gaucher disease [13] and Fabry disease [14], leading to significant advances in the understanding of lysosomal function and pathology [15]. Specifically, OMICs analyses have been successfully used in a variety of studies to identify disease-related changes in NPCD.…”

Section: Of 15mentioning

confidence: 99%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Comparative proteomic profiling reveals mechanisms for early spinal cord vulnerability in CLN1 disease

Cited by 11 publications

References 66 publications

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression

Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

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