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PICALM regulates cathepsin D processing and lysosomal function.

Kathryn J Hattersley1, Julian M Carosi1, Leanne K Hein1

  • 1Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.

Biochemical and Biophysical Research Communications
|July 26, 2021
PubMed
Summary
This summary is machine-generated.

Phosphatidylinositol-binding clathrin assembly protein (PICALM) is crucial for cellular waste clearance. Disrupting PICALM impairs lysosomal enzyme maturation and proteolysis, impacting cellular health and potentially Alzheimer's disease progression.

Keywords:
Alzheimer's diseaseAutophagyCathepsin DLysosomesPICALM

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Cellular waste degradation via autophagy and endo-lysosomal systems is vital for health and preventing diseases like Alzheimer's disease (AD).
  • Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a known AD risk gene, regulating autophagy initiation but its role in lysosomal enzyme maturation is unknown.

Purpose of the Study:

  • To investigate the role of PICALM in the maturation of lysosomal enzymes and cellular degradative function.
  • To determine the impact of PICALM disruption on proteolysis and autophagy.

Main Methods:

  • CRISPR/Cas9 was used to disrupt exon 1 of PICALM in HeLa cells.
  • Proteomic analysis of endosome-enriched samples and western blotting were employed to assess lysosomal enzyme abundance and cathepsin D processing.

Main Results:

  • PICALM disruption led to an increase in early endosomes.
  • Increased abundance of lysosomal enzymes was observed in endosomes, with impaired processing and maturation of cathepsin D.
  • A deficit in autophagy was also noted following PICALM disruption.

Conclusions:

  • PICALM plays a critical role in the correct maturation of lysosomal enzymes.
  • PICALM is essential for efficient proteolytic function within the lysosome.
  • These findings highlight PICALM's importance in cellular degradative processes and its potential implications for AD pathogenesis.