Neurotoxic stress; Garbage disposal V.S. landfill?

Neurons are pretty amazing cells. They are complicated and beautiful units of a massively complex network; and without them running at high efficiency I would struggle to remember critical facts such as ‘coffee is delicious’. Like any finely tuned machine, neurons need things to be in strict order. Proteins are where they need to be, and in the right amount. Neurons, like many other cells, have mechanisms that allow precise control of proteins and organelles under healthy conditions. The proteasome and lysosome are the not-so-glamorous stars of the waste management process1. I like to think of them as the garbage disposals of the cell: Breaking down excess or defective proteins and organelles for reuse, and generally keeping the cell as clutter-free as possible.

This is more than good housekeeping, when misfolded protein aggregates accumulate we tend to find neurological pathologies. Irregular proteins and dysfunctional mitochondria are both associated with age-related cognitive decline and neurological disorders such as Parkinson’s disease. What’s more, that old colloquialism “one bad apple can spoil the barrel” seems not to be too off target in this case; misfolded proteins appear to spread between neurons, although exactly how remains a bit of a mystery2. There are proposed models that explain parts of this damaged protein sharing and disease progression, but scientists still don’t have a complete picture.

A recent study by Melentijevic et al. may be shedding some light on this long-standing black box of protein (and organelle) transfer3. Using C elegans as a model system, the authors described an alternative waste disposal method in neurons. Rather than being degraded within the cell, harmful or excess proteins are selectively removed. Neurons were observed concentrating these aberrant proteins and then pinching off this portion of the cell. These exiled regions of the cell, termed exophers, remain connected to the cell body by thread-like tube that allows for shuttling of additional proteins and damaged components into the exopher. Eventually the exopher is released entirely from the cell, relegated to being a floating sack of biological junk and hazardous waste. It’s not a pretty picture, but there is an upshot, the neuron that uses the ‘land fill’ option has improved function. It makes a degree of sense, when neurons were genetically manipulated to express Hunntington’s protein aggregates or Alzheimer’s disease amyloid-beta fragment protein (both notoriously difficult to degrade through the proteasome), the cell had an alternative way of removing these disease associated aggregates.

Maybe this is a selfish act, that one neuron improves function, but what ever happens to the jettisoned membrane-bound garbage bag? Does it end up in a designated land fill, or does it find its way into someone else’s back yard? The authors found that coelomocytes, a specialized type of phagocytic leukocyte, would scavenge for, and degrade, the exophers; but if these disease proteins can find their way into distant coelmocytes, who is to say that they cant also find their way into neighboring neurons? It is speculative, but Melentijevic and colleagues argue that this may be a mechanism behind neurodegenerative disease progression. It is a fascinating possibility, but even if disproven these authors described a new method of protein homeostasis control, adding to our understanding of the biological complexity of neurons, and that is a pretty impressive achievement in itself.

  1. Tai, Hwan-Ching, and Erin M. Schuman. “Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction.” Nature Reviews Neuroscience 9.11 (2008): 826-838.
  2. Guo, Jing L., and Virginia MY Lee. “Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases.” Nature medicine 20.2 (2014): 130-138.
  3. Melentijevic, Ilija, et al. “C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress.” Nature 542.7641 (2017): 367-371.