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Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses
Science (New York, N.Y.)
|February 6, 1987
Summary
Lysosphingolipids reversibly inhibit protein kinase C (PKC) activity. Their accumulation in sphingolipidoses may explain disease pathogenesis by disrupting vital cellular signaling pathways.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Sphingolipids are crucial cellular components.
- Lysosphingolipids accumulate in various sphingolipidoses.
- The precise role of lysosphingolipids in disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate the effect of lysosphingolipids on protein kinase C (PKC) activity.
- To explore the potential link between lysosphingolipid accumulation and sphingolipidosis pathogenesis.
Main Methods:
- In vitro assays measuring protein kinase C activity.
- Analysis of phorbol dibutyrate binding.
- Mixed micelle assays to assess concentration-dependent effects.
Main Results:
- Lysosphingolipids potently and reversibly inhibited PKC activity and phorbol dibutyrate binding.
- Inhibition was dependent on molar percentage, not bulk concentration.
- Lysosphingolipids affected PKC at similar molar percentages as activators like phosphatidylserine.
Conclusions:
- Lysosphingolipid inhibition of PKC offers a functional link to sphingolipidosis pathogenesis.
- Accumulated lysosphingolipids may impair signal transduction, leading to neural dysfunction and cell death.
- This finding unifies existing data on sphingolipidosis mechanisms.