Urging neurons to self-eat: a therapy for neurodegenerative diseases?

Many bloggers like to write about studies that advance our understanding on how the brain FUNCTIONS, including myself. Function, however, depends on the smooth running of processes both between neurons (circuits) and within neurons. Unfortunately things don’t always go smoothly, and sometimes broken, misshapen and aggregated proteins can build up in cells, disrupting their normal function. This happens in many major neurodegenerative diseases, including Huntington’s, Parkinson’s, Alzheimer’s and Lou Gehrig's disease. While scientists don’t yet know if protein accumulation is the cause of the disease or a protective response against disease progression, we do know that eliminating these protein aggregates can (at least temporarily) alleviate symptoms, and in some cases, increase the lifespan of the individual (the latter has only been shown in flies though). Not surprisingly, there’s been considerable interest in upregulating protein degradation to treat these devastating diseases.

One major therapy hijacks an endogenous cellular process, autophagy, or “self-eating”. Autophagy is one of the ways cells spring clean. Proteins generally don’t last that long after they’re synthesized in cells. Think about it: milk spoils after a week in a 4C fridge. Proteins in neurons HAVE to operate at body temperature, are constantly bombarded with oxidants, macromolecular debris, and radiation. When they break to the point beyond repair, they get tagged for removal. In autophagy, certain proteins will recognize the tag (“adaptor proteins”), and through coordination with many different protein families, generate lipid “garbage bags” (called autophagosomes) around the broken proteins. The lipid vesicles are then trafficked along highways in the cell – microtubules – to the waste disposal center, the lysosome. The vesicles merge with the highly acidic lysosome, and the garbage is broken down and recycled. Organelles, such as ATP-generating mitochondria, can also be broken down in this way.  Autophagy can be activated in other conditions as well, such as starvation (to generate energy) or stroke.

Autophagy in a nutshell: make the garbage bag, transport the garbage to waste management facility, disposal/recycling of garbage

Breaking down too many cellular components is obviously bad for the cell. So the induction of autophagy is tightly controlled by cellular signals. One major inhibitor is mTORC, which is active during nutrient rich conditions. During starvation, mTORC becomes inhibited, and a second complex including Beclin-1 is activated, which then activates a group of proteins called the Vsp proteins in a cellular cascade, leading to formation of lipid vesicles. (TL;DR mTORC inhibitory, Beclin-1 stimulatory)

A common theme in neurodegenerative diseases is inhibition of autophagy. MANY things can go wrong with the process. In Alzheimer’s disease, mutated proteins can directly inhibit Beclin-1 complex thus locking up the “gas pedal”. The opposite holds for Huntington’s disease, where there is too much mTORC signaling, effectively stomping on the brake. Misshapen proteins aggregates may hide the “waste” tag, rendering adaptor proteins unable to recognize them. Or in the case of Huntington’s disease, mutant aggregates can “hog” too many adaptor proteins, hindering the degradation of other proteins. Sometimes autophagosomes can’t be trafficked properly; other times they can’t fuse with the lysosome, or the lysosome loses the enzymes necessary to degrade the cargo.

So what are some strategies currently tested to upregulate autophagy? One is to inhibit the “brake” mTORC with drugs such as rapamycin, or activate inhibitors of mTORC, such as Metformin (used clinically for Type II Diabetes). Other strategies aim to release Beclin-1 from intracellular compartments, so that it is more available to drive autophagy. Interestingly, several mood-regulating drugs including valproic acid (anti-seizure and mood stabilizer) and lithium (bipolar disorder) also seem to be effective at enhancing autophagy, though more research needs to be done.

A drug that can effectively and safely upregulate autophagy may be a promising cure for neurodegenerative diseases (as opposed to symptom management). While mutated protein aggregates may not be the cause for those diseases, eliminating them in various ways have time and again been shown to alleviate symptoms in animal disease models. Moving forward, there’re still many barriers to cross. One is to minimize side effects – most chemical inhibitors of mTORC are toxic since the complex is involved in other cellular processes as well. A potential strategy is to use peptide biomimetics, small peptides that mimick certain parts of a target protein required for function. For example, a recent paper in Nature described a small fragment of Beclin-1 that could induce autophagy by itself. These peptide drugs are considered to be much more specific and have fewer side effects than their chemical counterparts.

Another consideration is that upregulating autophagy may not be prudent in ALL disease cases. It really depends on where autophagy goes wrong. If induction is the problem, then upregulate away! However, if the problem is a defect in autophagosome trafficking or fusion with the lysosome, then upregulating autophagy would result in an accumulation of those garbage bags, which may be even more detrimental to the cell than aggregated proteins. (You want your garbage to go to the waste management facility, not get stuck on highways.)

Nevertheless, regulating autophagy may be one of the few ways to potentially treat multiple protein accumulation diseases regardless of initial reason of pathogenesis. It’s definitely a fast-developing field worth keeping an eye on.

Wong E, & Cuervo AM (2010). Autophagy gone awry in neurodegenerative diseases. Nature neuroscience, 13 (7), 805-11 PMID: 20581817
 

Shoji-Kawata, S., Sumpter, R., Leveno, M., Campbell, G., Zou, Z., Kinch, L., Wilkins, A., Sun, Q., Pallauf, K., MacDuff, D., Huerta, C., Virgin, H., Helms, J., Eerland, R., Tooze, S., Xavier, R., Lenschow, D., Yamamoto, A., King, D., Lichtarge, O., Grishin, N., Spector, S., Kaloyanova, D., & Levine, B. (2013). Identification of a candidate therapeutic autophagy-inducing peptide Nature, 494 (7436), 201-206 DOI: 10.1038/nature11866