Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease

Karayel, Özge; Winter, Sebastian Virreira; Padmanabhan, Shalini; Kuras, Yuliya I.; Vu, Duc Tung; Tuncali, Idil; Merchant, Kalpana; Wills, Anne‐Marie; Scherzer, Clemens R.; Mann, Matthias

doi:10.1016/j.xcrm.2022.100661

Cited by 81 publications

(74 citation statements)

References 99 publications

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“…Hence, we concluded that the truly organspecific damage upon a SARS-CoV-2 infection had to be separated from the blood proteome associated one to better understand tissue-specific effects in COVID-19. To do this, we made use of our previous work defining panels of different classes of proteins in body fluids (Geyer et al, 2016;Karayel et al, 2022). This analysis strategy indeed efficiently unmasked the tissue-specific effects of COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…Prompted by the ubiquitous predominance of systemic effects in COVID-19, we next investigated the possible contribution of the circulation-derived proteome in our tissue-based study and its impact on data interpretation. For this purpose, we employed proteomic 'quality control panels' which we had previously developed to control for the effect of blood compartment contamination in the proteomes of body fluids (Geyer et al, 2016;Karayel et al, 2022). We focused on representative markers of panels for coagulation, platelets, plasma and red blood cells (RBC).…”

Section: Deconvolution Of Organ-specific Effects In Covid-19mentioning

confidence: 99%

“…Marker proteins for coagulation, platelets and red blood cells (RBC) were extracted from (Karayel et al, 2022), the 30 most abundant and non-redundant proteins from the plasma were added from (Geyer et al, 2016). Proteins of this systemic-inflammatory response were complemented by immunoglobulins identified in our dataset (Supplementary Table 3).…”

Section: Bioinformatics Data Analysismentioning

confidence: 99%

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Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Schweizer

Schaller

Zwiebel

et al. 2022

Preprint

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SARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tissues. The first layer of response in all tissues was dominated by circulating inflammatory molecules. To discriminated between these systemic and true tissue-specific effects, we developed an analysis pipeline revealing that proteome alterations reflect extensive tissue damage, mostly similar to non-COVID diffuse alveolar damage. The next most affected organs were kidney and liver, while the lymph-vessel system was also strongly affected. Finally, secondary inflammatory effects of the brain correlated with receptor rearrangements and the degradation of neuronal myelin. Our results establish MS-based tissue proteomics as a promising strategy to inform organ-specific therapeutic interventions following COVID-19 infections.

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Section: Discussionmentioning

confidence: 99%

Section: Deconvolution Of Organ-specific Effects In Covid-19mentioning

confidence: 99%

Section: Bioinformatics Data Analysismentioning

confidence: 99%

See 1 more Smart Citation

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Schweizer

Schaller

Zwiebel

et al. 2022

Preprint

Self Cite

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“…It has to be noted however that these observations differ depending on the cancer type, and could therefore be explained by different immune reactions toward various cancer types. Regardless of the abundance of sHLA, several studies confirm their presence in different body fluids ( Table 1 ) ( 31 , 32 , 34 , 35 , 37 – 42 ). Interestingly, peptides bound to these sHLA are derived from intra- and extracellular proteins expressed in the cell of origin.…”

Section: Sourcing Biomarkers From Soluble Hla: Current Evidence and E...mentioning

confidence: 97%

Soluble HLA peptidome: A new resource for cancer biomarkers

2022

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Using circulating molecular biomarkers to screen for cancer and other debilitating disorders in a high-throughput and low-cost fashion is becoming increasingly attractive in medicine. One major limitation of investigating protein biomarkers in body fluids is that only one-fourth of the entire proteome can be routinely detected in these fluids. In contrast, Human Leukocyte Antigen (HLA) presents peptides from the entire proteome on the cell surface. While peptide-HLA complexes are predominantly membrane-bound, a fraction of HLA molecules is released into body fluids which is referred to as soluble HLAs (sHLAs). As such peptides bound by sHLA molecules represent the entire proteome of their cells/tissues of origin and more importantly, recent advances in mass spectrometry-based technologies have allowed for accurate determination of these peptides. In this perspective, we discuss the current understanding of sHLA-peptide complexes in the context of cancer, and their potential as a novel, relatively untapped repertoire for cancer biomarkers. We also review the currently available tools to detect and quantify these circulating biomarkers, and we discuss the challenges and future perspectives of implementing sHLA biomarkers in a clinical setting.

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“…The link between lysosomal dysfunction and PD is bolstered by an increased burden of variants in several genes that cause rare monogenic lysosomal storage disorders (LSDs) in PD patients, suggesting common mechanisms of lysosomal dysfunction drive both severe LSDs and PD(6-8). Defects in lysosomal homeostasis have also been observed in PD patient postmortem brain samples or biofluids, including depletion of the lysosomal compartment, glycosphingolipid (GSL) storage, and accumulation of lysosomal proteins (9-13). These data suggest that approaches aimed at correcting lysosomal dysfunction may provide new therapeutic avenues for the treatment of PD, for which there still remains no disease-modifying therapy.…”

Section: Introductionmentioning

confidence: 99%

LRRK2 Kinase Activity Regulates Parkinson’s Disease-Relevant Lipids at the Lysosome

Maloney

Wang

Ghosh

et al. 2022

Preprint

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Lysosomal dysfunction is a hallmark of Parkinson's disease (PD), and variants in several PD-associated genes, including LRRK2, perturb lysosomal homeostasis. Based on this, LRRK2 kinase inhibition is being explored as a therapeutic approach for the treatment of PD. LRRK2 inhibitors reduce levels of BMP, an endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in urine from preclinical models and clinical subjects, however, the mechanisms by which LRRK2 regulates BMP and the functional significance of this change to disease are undefined. We establish that LRRK2 regulates secretion of BMP- and GSL-containing vesicles from kidney into urine and modulates BMP and GSL levels in the brain. BMP accumulates within lysosomes as a secondary response to LRRK2's effects on the activity of glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism. Alterations in BMP and GCase substrate turnover are observed in CSF from LRRK2-PD patients, highlighting the relevance of LRRK2-dependent lysosomal dysfunction in disease.

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Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease

Cited by 81 publications

References 99 publications

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Soluble HLA peptidome: A new resource for cancer biomarkers

LRRK2 Kinase Activity Regulates Parkinson’s Disease-Relevant Lipids at the Lysosome

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