The chaperone Clusterin in neurodegeneration−friend or foe?

Yuste-Checa, Patricia; Bracher, A.; Fu, Hartl

doi:10.1002/bies.202100287

Cited by 24 publications

(20 citation statements)

References 190 publications

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“…This suggests that an imbalance between complement activation and regulation may be ongoing in the gray matter of patients with progressive MS. The upregulation of Clu provides evidence for the suppression of the terminal complement in cortical areas ( 66 ). However, in contrast to prior studies, C9neo+ neurons were elevated in deep cortical and subpial lesions in comparison to non-inflammatory controls, indicating that at least to some degree, MAC formation may occur in the gray matter.…”

Section: Complement In the Gray Matter And Hippocampus: Synaptic Prun...mentioning

confidence: 99%

The role of the complement system in Multiple Sclerosis: A review

Saez-Calveras

Stüve

2022

Front. Immunol.

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The complement system has been involved in the pathogenesis of multiple neuroinflammatory and neurodegenerative conditions. In this review, we evaluated the possible role of complement activation in multiple sclerosis (MS) with a focus in progressive MS, where the disease pathogenesis remains to be fully elucidated and treatment options are limited. The evidence for the involvement of the complement system in the white matter plaques and gray matter lesions of MS stems from immunohistochemical analysis of post-mortem MS brains, in vivo serum and cerebrospinal fluid biomarker studies, and animal models of Experimental Autoimmune Encephalomyelitis (EAE). Complement knock-out studies in these animal models have revealed that this system may have a “double-edge sword” effect in MS. On the one hand, complement proteins may aid in promoting the clearance of myelin degradation products and other debris through myeloid cell-mediated phagocytosis. On the other, its aberrant activation may lead to demyelination at the rim of progressive MS white matter lesions as well as synapse loss in the gray matter. The complement system may also interact with known risk factors of MS, including as Epstein Barr Virus (EBV) infection, and perpetuate the activation of CNS self-reactive B cell populations. With the mounting evidence for the involvement of complement in MS, the development of complement modulating therapies for this condition is appealing. Herein, we also reviewed the pharmacological complement inhibitors that have been tested in MS animal models as well as in clinical trials for other neurologic diseases. The potential use of these agents, such as the C5-binding antibody eculizumab in MS will require a detailed understanding of the role of the different complement effectors in this disease and the development of better CNS delivery strategies for these compounds.

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Section: Complement In the Gray Matter And Hippocampus: Synaptic Prun...mentioning

confidence: 99%

The role of the complement system in Multiple Sclerosis: A review

Saez-Calveras

Stüve

2022

Front. Immunol.

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“…As a final analysis, we compared the mean normalised Intensity Based Absolute Quantification (iBAQ) values from selected individual proteins from SEC fractions 3-5 (Figure 4D) . First group was apolipoproteins involved in the structures of HDL, low-density lipoproteins (LDL), chylomicrons, and ApoJ (Clusterin) which is connected to several neurodegenerative diseases (Yuste-Checa et al, 2022; Feingold, 2000). All apolipoproteins had highest intensities in fractions 4 and 5, indicating a presence of lipoprotein particles.…”

Section: Resultsmentioning

confidence: 99%

Towards optimised extracellular vesicle proteomics from cerebrospinal fluid

Kangas

Nyman

Metsähonkala

et al. 2022

Preprint

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The proteomic profile of extracellular vesicles (EVs) from cerebrospinal fluid (CSF) can reveal novel biomarkers for diseases of the brain. Here, we validate an ultrafiltration combined with size-exclusion chromatography (UF-SEC) method for isolation of EVs from canine CSF and probe the effect of starting volume on the EV proteomics profile. First, we performed a literature review of CSF EV articles to define the current state of art, discovering a need for basic characterisation of CSF EVs. Secondly, we isolated EVs from CSF by UF-SEC and characterised the SEC fractions by protein amount, particle count, transmission electron microscopy, and immunoblotting. Data are presented as mean ± standard deviation. Using proteomics, SEC fractions 3-5 were compared and enrichment of EV markers in fraction 3 was detected, whereas fractions 4-5 contained more apolipoproteins. Lastly, we compared starting volumes of pooled CSF (6ml, 3ml, 1ml, and 0.5ml) to evaluate the effect on the proteomic profile. Even with a 0.5ml starting volume, 743±77 or 345±88 proteins were identified depending on whether 'matches between runs' was active in MaxQuant. The results confirm that UF-SEC effectively isolates CSF EVs and that EV proteomic analysis can be performed from 0.5ml of canine CSF.

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“…In addition, SIAH3 has been associated through another GWAS to rate of ventricular enlargement in the ADNI cohort [45], an association that has also been separately observed with variants near CLU [46]. Taken together, these observations, along with evidence for diverse contributions of clusterin in LOAD (recently review in [47]), suggest that further investigation of the role of clusterin and processes that may influence the effects of clusterin in ADAD is warranted.…”

Section: Discussionmentioning

confidence: 97%

Genetic Associations with Age at Dementia Onset in thePSEN1 E280AColombian Kindred

Cochran

Acosta‐Uribe

Madrigal

et al. 2020

Preprint

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Background: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) have revealed genetic variants with the potential for therapeutic application. Such studies in late onset AD are limited by population heterogeneity and co-morbidities associated with aging. Studies to date in ADAD (autosomal dominant AD) have been limited by their small sample size. The large Colombian kindred presented here provides a unique opportunity to discover AAO genetic associations. Methods: A genetic association study was conducted for AAO in 344 individuals with the PSEN1 E280A mutation via array imputation and whole genome sequencing in a subset of 80 individuals. Scrambled age conditions were used as a control, and replication was assessed using three studies on AD age of onset, age of onset survival, and meta-analysis. Results: The proportion of variance explained (+/- 95% CI) was 56% (+/-15%). 29 loci reached genome-wide significance, of which 23 had a GWAS hit from the NHGRI-EBI catalog within 500 kb relevant to neurodegeneration. Hits included a new variant in the CLU locus, rs35980966, (which replicated), a variant in a locus on a separate chromosome previously associated with plasma clusterin (rs138295139), and a missense variant in SORBS3 (rs34059820). Former GWAS index variants at the CLU locus also replicated in this cohort (rs4236673, rs9331896). APOE ϵ4 (rs429358) and APOE ϵ2 (rs7412)-associated variants exhibited modest (less than 3 years) associations with earlier and later age of dementia onset, respectively. Other nominal associations included coding variants in IL34 (rs4985556), TSPAN10 (rs6565617, rs7210026), STIM2 (rs1457401458), HTT (rs1473464204), and KCNT1 (rs557219607). Interpretation: A large proportion of the variability in AAO was explained by genetic variation at numerous loci. The unique demography of this population as a tri-continental admixture that passed through a bottleneck about 500 years ago might predict that drift would uncover rare variants with a large effect size on AAO. Indeed, candidates for large contributions from rare alleles were observed. Common variation, presumably ancestral to the bottleneck, was also associated with AAO. The detection of these effects in the presence of a strong mutation for ADAD reinforce the potentially impactful role of the identified variants.

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The chaperone Clusterin in neurodegeneration−friend or foe?

Cited by 24 publications

References 190 publications

The role of the complement system in Multiple Sclerosis: A review

The role of the complement system in Multiple Sclerosis: A review

Towards optimised extracellular vesicle proteomics from cerebrospinal fluid

Genetic Associations with Age at Dementia Onset in thePSEN1 E280AColombian Kindred

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