Deciphering metabolic shifts in Gaucher disease type 1: a multi-omics study

Area of Science:

• Biochemistry
• Immunology
• Genetics

Background:

• Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by deficient β-glucocerebrosidase (GCase).
• This deficiency leads to glucosylceramide accumulation, resulting in diverse clinical manifestations.
• Understanding the biochemical landscape of GD is crucial for developing targeted therapies.

Purpose of the Study:

• To comprehensively investigate the biochemical and immune profiles in type 1 Gaucher disease patients.
• To identify novel biomarkers and understand the molecular mechanisms underlying GD pathogenesis.
• To correlate omics features with clinical traits and treatment status.

Main Methods:

• Immune-based proteomics and mass spectrometry-based metabolomics were employed.
• 43 type 1 GD patients and 59 controls were deeply phenotyped.
• Conventional and systems biology approaches were used for data analysis.

Main Results:

• Elevated phosphatidylcholines indicate altered lipid metabolism and endoplasmic reticulum stress.
• GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation.
• Mitochondrial dysfunction is suggested by oxidative stress markers and altered acylcarnitine profiles.

Conclusions:

• Autophagy inhibition, through chronic mTORC1 activation, is pivotal in GD, driving lipid synthesis, mitochondrial dysfunction, and inflammation.
• Specific omics features correlate with clinical traits like platelet count and splenectomy, offering potential diagnostic markers.
• This study provides valuable insights into GD's metabolic and immune dysregulation, paving the way for future research.