Clusterin: Always protecting. Synthesis, function and potential issues

Rodríguez-Rivera, Carmen; García, Miguel Martínez; Molina-Álvarez, Miguel; González‐Martín, Carmen; Goicoechea, Carlos

doi:10.1016/j.biopha.2020.111174

Cited by 67 publications

(44 citation statements)

References 100 publications

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“…Clusterin is an extracellular protein chaperone that is activated during inflammation and disease ( Satapathy and Wilson, 2021 ). However, its relevance to NCL is unclear since it is one of the most broadly identified biomarkers in a variety of diseases ( Rodríguez-Rivera et al, 2021 ). Another potential biomarker, myoglobin, is released into the circulation upon muscle damage, including from the myocardium ( Guerrero-Hue et al, 2018 ), which is consistent with the cardiac defects associated with CLN3 disease ( Rietdorf et al, 2020 ).…”

Section: Potential Biomarkers Identified In Animal Models and Humansmentioning

confidence: 99%

Altered protein secretion in Batten disease

Huber

2021

Disease Models &Amp; Mechanisms

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The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

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Section: Potential Biomarkers Identified In Animal Models and Humansmentioning

confidence: 99%

Altered protein secretion in Batten disease

Huber

2021

Disease Models &Amp; Mechanisms

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“…Clusterin, fetuin-A, and TREM-2 are examples of biomarkers linked to delays in the progression of neurodegeneration [ 86 , 91 , 92 , 93 ]. The depletion of these factors results in the progression of neurodegenerative disorders and excess cerebrovascular strokes [ 85 , 86 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. Apolipoprotein E (apoE) was frequently linked to dementia progression in general, but in COVID-19, this factor may be of particular importance [ 98 ].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

et al. 2021

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The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2′s neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid β42, TDP43, NF-L, and KLK6 serum levels declined 2–3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3–7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-β40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

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“…Clusterin is a disulphide-linked heterodimeric protein that plays an anti-apoptotic role in the cells. 1 Clusterin plays the role of a chaperone, which enables proteins to be secreted by folding their structure. Through this mechanism, clusterin facilitates the activity of pro-apoptotic and anti-apoptotic entities.…”

Section: Introductionmentioning

confidence: 99%

“…Through this mechanism, clusterin facilitates the activity of pro-apoptotic and anti-apoptotic entities. 1 Additionally, clusterin has been reported to play anti-inflammatory roles by downregulating the transcriptional activity of nuclear factor-kappa B (NF-κB) in several systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. 2 Moreover, the concentration of clusterin was reported to be low in both active rheumatoid arthritis and systemic lupus erythematosus due to the regulation of and loss of ability to inactivate lupus-specific complements, respectively.…”

Section: Introductionmentioning

confidence: 99%

Serum Clusterin Level Could Reflect the Current Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

et al. 2021

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Purpose We investigated whether serum clusterin levels could reflect the current antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices. Materials and Methods Fifty-seven patients with AAV and 40 healthy controls were included in this study. AAV-specific indices included the Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and MCS) scores, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and vasculitis damage index. Clinical and laboratory data and AAV-specific indices were obtained at blood collection. The highest tertile of BVAS (≥16) was defined as high activity of AAV. Results The median age of AAV patients was 64.0 years and 19 patients were male. SF-36 PCS score (r=0.328), SF-36 MCS score (r=0.289), BVAS (r=−0.404), erythrocyte sedimentation rate (r=−0.336), and C-reactive protein levels (r=−0.421) were significantly correlated with serum clusterin levels. In the multivariable linear regression analysis using AAV-specific indices and serum clusterin levels, both FFS (β=0.412) and serum clusterin levels (β=−0.250) were significantly associated with BVAS. When the optimal serum clusterin cut-off level for high activity of AAV was identified as 130.45 µg/mL, patients with serum clusterin level ≤130.45 µg/mL had a significantly higher risk for high activity of AAV than did those without (relative risk 7.194). Patients with AAV exhibited significantly lower serum clusterin levels than did healthy controls (168.2 µg/mL vs. 230.5 µg/mL). Conclusion Serum clusterin levels could reflect the current disease activity in patients with AAV.

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Clusterin: Always protecting. Synthesis, function and potential issues

Cited by 67 publications

References 100 publications

Altered protein secretion in Batten disease

Altered protein secretion in Batten disease

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

Serum Clusterin Level Could Reflect the Current Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

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