Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system

Bell, Andrew S.; Wagner, Josephin; Rosoff, Daniel B.; Lohoff, Falk W.

doi:10.1016/j.neubiorev.2023.105155

Cited by 18 publications

(12 citation statements)

References 175 publications

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“…PCSK9 is a serine protease consisting of four parts: a signal peptide, a prestructural domain, a catalytic structural domain, and a C‐terminal cysteine/histidine‐rich structural domain, 65,66 which is mainly produced by the liver and secreted into the bloodstream 67 . In addition, there is low expression in the intestinal tract, central nervous system, and renal mesenchymal stromal cells 67,68 . The link between PCSK9 and cholesterol metabolism was first identified in PCSK9‐overexpressing wild‐type mice, 67 which had increased plasma triglyceride (TG) and cholesterol‐rich LDL (LDL‐C) levels, whereas hepatic low‐density lipoprotein receptor (LDLR) was virtually absent 67 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…When PCSK9 is not present, the LDLR loops multiple times 68 . (B) Monoclonal antibodies (e.g., alirocumab) that bind to and inhibit soluble PCSK9 in plasma, preventing PCSK9 from binding to LDLR and causing LDLR to be degraded by the lysosome 68 . (C) RNAi reagents (e.g., inclisiran) that prevent successful translation of PCSK9 mRNA, thereby reducing the amount of mature PCSK9 bound to LDLR 68 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…It is currently believed that the effects of PCSK9 on lipid metabolism are primarily mediated through the regulation of hepatic LDLR levels (Figure 2A). 68,82 …”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…(A) When PCSK9 is present, circulating PCSK9 binds to LDLR and LDL particles through its catalytic structural domains, sequestering the LDLR for degradation in the lysosome, which in turn upregulates LDL‐C levels. When PCSK9 is not present, the LDLR loops multiple times 68 . (B) Monoclonal antibodies (e.g., alirocumab) that bind to and inhibit soluble PCSK9 in plasma, preventing PCSK9 from binding to LDLR and causing LDLR to be degraded by the lysosome 68 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…(B) Monoclonal antibodies (e.g., alirocumab) that bind to and inhibit soluble PCSK9 in plasma, preventing PCSK9 from binding to LDLR and causing LDLR to be degraded by the lysosome 68 . (C) RNAi reagents (e.g., inclisiran) that prevent successful translation of PCSK9 mRNA, thereby reducing the amount of mature PCSK9 bound to LDLR 68 . (D) In vivo gene editing of PCSK9 to induce host cell DNA double‐strand breaks to reduce PCSK9 gene expression 68 .…”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

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Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

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Drug development is a long and costly process, with a high degree of uncertainty from the identification of a drug target to its market launch. Targeted drugs supported by human genetic evidence are expected to enter phase II/III clinical trials or be approved for marketing more quickly, speeding up the drug development process. Currently, genetic data and technologies such as genome‐wide association studies (GWAS), whole‐exome sequencing (WES), and whole‐genome sequencing (WGS) have identified and validated many potential molecular targets associated with diseases. This review describes the structure, molecular biology, and drug development of human genetics‐based validated beneficial loss‐of‐function (LOF) mutation targets (target mutations that reduce disease incidence) over the past decade. The feasibility of eight beneficial LOF mutation targets (PCSK9, ANGPTL3, ASGR1, HSD17B13, KHK, CIDEB, GPR75, and INHBE) as targets for drug discovery is mainly emphasized, and their research prospects and challenges are discussed. In conclusion, we expect that this review will inspire more researchers to use human genetics and genomics to support the discovery of novel therapeutic drugs and the direction of clinical development, which will contribute to the development of new drug discovery and drug repurposing.

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Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

“…It is currently believed that the effects of PCSK9 on lipid metabolism are primarily mediated through the regulation of hepatic LDLR levels (Figure 2A). 68,82 …”

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

Section: Drug Development Of Targets Based On Gwas Wgs and Wes Discov...mentioning

confidence: 99%

See 3 more Smart Citations

Drug development advances in human genetics‐based targets

Zhang,

Yu,

et al. 2024

MedComm

View full text Add to dashboard Cite

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Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence

Zhu,

Xu,

et al. 2023

Drug Development Research

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low‐density lipoprotein cholesterol (LDL‐C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL‐C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.

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