A two-dimensional protein fragmentation-proteomic study of neuronal ceroid lipofuscinoses: Identification and characterization of differentially expressed proteins

Wang, Peirong; Ju, Weina; Wu, Dan; Wang, Li; Yan, Ming; Zhang, Junhua; He, Bing; Jenkins, Edmund C.; Brown, W. Ted; Zhong, Nanbert

doi:10.1016/j.jchromb.2010.12.011

Cited by 8 publications

(7 citation statements)

References 53 publications

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“…Integrative system-based proteomics approaches have been utilized for studies of neurodegenerative disorders, including NCL. Wang et al (2011) profiled disease-related changes by combining two-dimensional electrophoresis with mass spectrometry in NCL-derived fibroblast cell lines. This work revealed changes related to multiple cellular functional categories, including: cell motility and development, apoptosis, membrane trafficking and calcium binding, but the identified changes were not validated in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules

et al. 2015

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Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood encephalopathy.

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Section: Introductionmentioning

confidence: 99%

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules

et al. 2015

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“…CLN3 patient fibroblasts (C8614 and C9282) were obtained from the laboratory of late Dr. K. E. Wisniewski, New York State Institute for Basic Research. These patient cells have identical mutations (ie, homozygous 1.02 kb deletion in the CLN3 gene) as previously reported . Normal and CLN3 patient fibroblasts were cultured in Dulbecco's Modified Eagle Medium (DMEM) (ThermoFisher scientific; Cat # 11965‐092) with 10% fetal bovine serum (FBS) and 1% Penstrep (ThermoFisher scientific; Cat # 15140‐122).…”

Section: Methodsmentioning

confidence: 99%

Cln3‐mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl‐protein thioesterases‐1 (Ppt1)‐protein and Ppt1‐enzyme activity in the lysosome

Appu

Bagh

Sadhukhan

et al. 2019

J of Inher Metab Disea

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Mutations in at least 13 different genes (called CLNs) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the CLN1 gene, encoding palmitoyl‐protein thioesterases‐1 (PPT1), cause infantile NCL (INCL), those in the CLN3 gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S‐palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1‐deficiency causes lysosomal accumulation of autofluorescent ceroid leading to INCL. Because intracellular accumulation of ceroid is a characteristic of all NCLs, a common pathogenic link for these diseases has been suggested. It has been reported that CLN3‐mutations suppress the exit of cation‐independent mannose 6‐phosphate receptor (CI‐M6PR) from the trans Golgi network (TGN). Because CI‐M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that CLN3‐mutations may cause lysosomal PPT1‐insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in Cln3‐mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1‐protein and Ppt1‐enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v‐ATPase, which regulates lysosomal acidification, is mislocalized to the plasma membrane instead of its normal location on lysosomal membrane. This defect dysregulates lysosomal acidification, as we previously reported in Cln1 −/− mice, which mimic INCL. Our findings uncover a previously unrecognized role of CLN3 in lysosomal homeostasis and suggest that CLN3‐mutations causing lysosomal Ppt1‐insuffiiciency may at least in part contribute to JNCL pathogenesis.

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“…In an early study of NCL3 patient fibroblasts, Wang and colleagues 172 describe altered proteins associated with apoptosis, cytoskeleton, membrane trafficking, calcium-binding nucleosome assembly, and cell development. 172 Interestingly, This journal is © The Royal Society of Chemistry 2022 a two-dimensional protein fragmentation-proteomic data showed annexin A1 and vimentin were downregulated in NCL3 fibroblasts, where L-caldesmon, which has an actin-binding domain, 173 was upregulated at both the protein and mRNA level, indicating a potential disturbance of the cell motility in NCL3 patient fibroblasts. 172 It is known that the deficiency of PPT1 can cause CLN1, however, PPT1 was upregulated in a CLN3 patient autopsy brain and CSF samples, 154 which may become a potential biomarker for differentiating from different types of NCLs (Table 1).…”

Section: Cln3mentioning

confidence: 99%

“…172 Interestingly, This journal is © The Royal Society of Chemistry 2022 a two-dimensional protein fragmentation-proteomic data showed annexin A1 and vimentin were downregulated in NCL3 fibroblasts, where L-caldesmon, which has an actin-binding domain, 173 was upregulated at both the protein and mRNA level, indicating a potential disturbance of the cell motility in NCL3 patient fibroblasts. 172 It is known that the deficiency of PPT1 can cause CLN1, however, PPT1 was upregulated in a CLN3 patient autopsy brain and CSF samples, 154 which may become a potential biomarker for differentiating from different types of NCLs (Table 1). Calbindin 1 (CALB1, or calbindin D28), a calciumbinding protein expressed in the cerebellum (proposed as a potential biomarker for cerebellar disease progression in NPC1 disease) 174 was also increased in CLN3 CSF samples 154 (Table 1).…”

Section: Cln3mentioning

confidence: 99%

Mass spectrometry-based proteomics in neurodegenerative lysosomal storage disorders

Cologna

2022

Mol. Omics

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A two-dimensional protein fragmentation-proteomic study of neuronal ceroid lipofuscinoses: Identification and characterization of differentially expressed proteins

Cited by 8 publications

References 53 publications

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules

Cln3‐mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl‐protein thioesterases‐1 (Ppt1)‐protein and Ppt1‐enzyme activity in the lysosome

Mass spectrometry-based proteomics in neurodegenerative lysosomal storage disorders

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