Lecture 3 - phospholipidosis Flashcards
What is phospholipidosis?
its a lysosomal storage disorder characterized by excess accumulation of lipids
What are lamellar bodies?
histological hallmark of phospholipidosis and mostly reflect a disease or a toxicity
What are the basics of lysosomes?
exist in all cells except erthyrocytes. pH is around 4.5-4.8 kept in check by H+ pumps (ABC transporter) and contain many enzymes (proteases, lipases etc)
What are lysosomes function
Autophagy and heterophagy
What are the types of heterophagy (2)
Phagocytosis and endocytosis
What are the 3 types of autophagy?
macrophagy, microphagy and chaperon-mediated autophagy
What is the role of lysosomes in recycling the LDL-receptor
When LDL receptors are not bound they are recycled. When LDL are bound to PCSK9 (through autolytic cleavage or proPCSK9) they are shuttled to a lysosome for degradation
What are the roles of lysosomes in mitophagy?
They destroy trapped mitochondria (phagophore membrane formation from PINK1/Parkin or BNIP3/NIX)
How do lysosomes play a role in cell death?
LMP leading to acidification of cytoplasm and caspase activation from cathepsin (in cytosol)
Examples of lysosomal storage diseases.
Niemann Pick, Tay-Sachs and Fabry disease
Why can cationic amphiphilic drugs enter lysosomes?
CAD structure is lipophilic ring structure with a polar side chain. Is uncharge when entering lysosome but in acidic pH it becomes protonated (taking a H+) and is now trapped.
How do CADS increase phospholipidosis?
CADs can bind to phospholipids and render then indigestible for phospholipases.
They can also prevent enzymes such as LPLA2 from binding to the lysosome membrane by altering its charge.
How do you detect phospholipidosis?
Electron microscopy (gold std.)
In silic
fluorescent phospholipids in vitro
BMP accumulation in vivo
How do aminoglycosides cause phospholipidosis?
by interfering with megalin/cubilin system and preventing lysosomal degradation of megalin/cubilin-substance complexes
