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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
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Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian

Qiang Huang1,2, Qin Zhang1, Bei Cao1

  • 1Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Brain and Behavior
|June 5, 2024
PubMed
Abstract

Insights

Proprotein convertase subtilis kexin 9 (PCSK9) inhibitors reduce amyotrophic lateral sclerosis (ALS) risk but increase Parkinson's disease (PD) risk. HMGCR inhibitors also appear to increase PD risk, warranting further investigation.

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Proprotein convertase subtilis kexin 9 (PCSK9) inhibitors have pleiotropic effects beyond cholesterol reduction, including potential neuroprotective roles.
  • The impact of PCSK9 inhibitors on neurodegenerative diseases remains controversial, necessitating rigorous investigation.
  • Understanding these effects is crucial for developing targeted therapies for conditions like ALS, PD, and AD.

Purpose of the Study:

  • To investigate the causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases using a drug-targeted Mendelian randomization (MR) approach.
  • To compare the effects of PCSK9 inhibitors with 3-Hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statins) on neurodegenerative disease risk.
  • To evaluate the specific impacts on amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).

Main Methods:

  • Utilized single nucleotide polymorphisms (SNPs) associated with PCSK9 from genome-wide association studies.
  • Performed drug-target Mendelian randomization (MR) analysis to infer causal effects.
  • Employed coronary heart disease risk as a positive control and analyzed outcomes for ALS, PD, and AD.

Main Results:

  • PCSK9 inhibitors showed a marginal risk reduction for ALS (OR = 0.89, p = 0.048).
  • PCSK9 inhibitors were associated with an increased risk of PD (OR = 1.417, p = 0.004).
  • HMGCR inhibitors also demonstrated an increased risk for PD (OR = 1.907, p = 0.001).

Conclusions:

  • PCSK9 inhibitors significantly reduce ALS risk but elevate PD risk.
  • HMGCR inhibitors may represent a risk factor for Parkinson's disease.
  • Further research is warranted to elucidate the complex relationship between these drug classes and neurodegenerative disease pathogenesis.
Keywords:
HMGCRPCSK9drug target Mendelian randomizationneurodegenerative diseases

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