Several well-known neurodegenerative diseases, such as Lou Gehrig’s (ALS), Parkinson’s, Alzheimer’s, and Huntington’s disease, all result in part from a defect in autophagy – one way a cell removes and recycles misfolded proteins and pathogens. In a paper published this week in Current Biology, postdoctoral fellow David Kast, PhD, and professor Roberto Dominguez, PhD, and three other colleagues from the Department of Physiology at the Perelman School of Medicine at the University of Pennsylvania, show for the first time that the formation of ephemeral compartments key in this process require actin polymerization by the Arp2/3 complex, a composite of seven proteins.
They found that the cell recycling machinery is regulated by a protein called WHAMM, and that interfering with this protein or actin polymerization itself severely inhibits the cell’s ability to recycle misfolded proteins and damaged organelles via autophagy. This is particularly important for non-dividing neurons, because the accumulation of waste leads to impaired intercellular communication and neurodegeneration.
“Cells are very good at recycling and sorting cellular trash into the correct recycling bins,” Dominguez says. “Cells sequester trash in compartments called autophagosomes” Cells follow a set recipe for recycling: First, the autophagosome is formed around the trash, next autophagosomes are transported and merged with lysosomes – another cellular compartment – and finally, the contents are degraded and either secreted or reused by the cell.
The Penn team found that this recycling process is fueled by the actin cytoskeleton, whose major component is the protein actin itself. Autophagosomes arise from the endoplasmic reticulum (ER) — a network of tubular membranes – and actin dynamics is key in their formation and movement.
The “fuel” for the biogenesis and movement of autophagosomes is provided by actin polymerization powered by the Arp2/3 complex, which is recruited to autophagosomes by WHAMM. Polymerization is the chemical reaction that allows for the formation of molecular chains, in this case, actin filaments.
Source: University of Pennsylvania