New inducers of autophagy—the process by which cells use lysosomes to degrade portions of their cytoplasm—are lead compounds for new drugs targeting neurodegenerative protein aggregation diseases.
Induction of a process that augments the cell's capacity to degrade intracellular protein aggregates is a goal in therapy of neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's disease. These diseases are characterized by accumulation of intracellular protein aggregates in nerve cells, which ultimately cause cell death and ensuing loss of brain functions1,2. On p. 331 of this issue, Sarkar et al.3 describe a set of new neuroprotective compounds that stimulate the cell's digestion of protein aggregates.
One of the major cellular pathways for scavenging intracellular protein aggregates is autophagy (literally, “self-eating”)2. Autophagy is a bulk degradation process that involves the sequestration of portions of cytoplasm by a double-membrane autophagosome, followed by digestion of the sequestered material when the autophagosome fuses with a lysosome full of hydrolytic enzymes (Fig. 1)4. Recently, researchers found that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins5,6, which suggests that the continuous clearance of cellular proteins through basal autophagy prevents their accumulation, and in turn prevents neurodegeneration. Experiments in fly and mouse models have provided proof of principle that stimulation of autophagy can prevent and even reverse neurodegenerative disease7.
The compound that has been used for such studies, the immunosuppressant rapamycin, stimulates autophagy and aggregate digestion by inhibiting the evolutionarily conserved protein kinase TOR (target of rapamycin)2. Via a mechanism that remains to be clarified, TOR acts as a brake on autophagy; thus, when it is inhibited with rapamycin, autophagy is turned on. Unfortunately, TOR does not control autophagy alone—it is also an activator of ribosome biogenesis and other pathways involved in cell growth (Fig. 1)8. This causes undesired side effects (immunosuppression may be considered a side effect in this context) during long-term administration of rapamycin, and therefore alternative inducers of autophagy are desired.
As an approach to obtaining new compounds that modulate autophagy, Sarkar et al. performed a small-molecule screen in yeast for compounds that either enhance or inhibit the growth-inhibitory effect of rapamycin in this organism. Out of more than 50,000 compounds screened, the authors identified 12 small-molecule enhancers of rapamycin (SMERs)3. When these were tested in mammalian-cell systems for their ability to mediate clearance of mutant huntingtin and α-synuclein proteins associated with Huntington's disease and familial Parkinson's disease, respectively, three of these (SMERs 10, 18 and 28) were found to increase clearance of these known autophagy substrates. Studies with mouse embryonic fibroblasts lacking Atg5, a crucial component of the autophagic machinery, confirmed that autophagy is required for this activity of the SMERs. The authors then went on to demonstrate that SMERs 10, 18 and 28 induce autophagy in mammalian cells, and finally they showed that these compounds reverse the toxic effects of mutant huntingtin on photoreceptors in the fly eye, thus providing proof of principle that the SMERs can reverse aggregation toxicity in vivo.
So how do the SMERs work? Sarkar et al.3 established that they act synergistically with rapamycin in autophagic protein aggregate clearance in mammalian cells, which is consistent with the way they were identified in the yeast screen. Moreover, none of the three selected SMERs affected the phosphorylation of two canonical TOR substrates involved in protein synthesis. Although we cannot exclude the possibility that the SMERs influence some uncharacterized pathway downstream of TOR, it is more likely that they stimulate autophagy by a novel TOR-independent mechanism (Fig. 1). Insulin receptor substrate 2, a scaffold protein involved in insulin and insulin-like growth factor 1 signaling, has recently been shown to cause autophagic clearance of accumulated mutant huntingtin despite activation of TOR9, and it is possible that SMERs act in this same pathway.
There is still some way to go before we know whether the SMERs and their derivatives can serve as valuable drug leads. The compounds will have to be tested for efficacy and toxicity in suitable animal models for neurodegenerative diseases, and because the SMERs enhanced rapamycin's growth-inhibitory effect in yeast, possible growth-inhibitory effects in mammals need to be monitored carefully. SMERs will almost certainly have to be derivatized before further development, and Sarkar et al. have already proven the feasibility of a structure-activity relationship–based protocol for improvement of the SMERs3. However, in order to further investigate their clinical potential, it will be crucial to know more about the precise mechanism of action of the SMERs, as this not only will hint about routes to optimize the activity of the compounds while minimizing possible side effects, but also may shed new light on the way autophagy is controlled.
The identification of the SMERs as autophagy-inducing drugs is exciting because it may bring us closer to a new therapy for neurodegenerative diseases, for which current pharmacotherapy is insufficient. Moreover, the growth-inhibitory effects that rapamycin and its synthetic analogs have on certain cancers may in part be attributed to their autophagy-inducing effects10. The identification of novel autophagy inducers could therefore also provide us with new possibilities for treating cancer in the future.
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The authors declare no competing financial interests.
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Simonsen, A., Stenmark, H. Stimulating the cell's appetite for itself. Nat Chem Biol 3, 304–306 (2007). https://doi.org/10.1038/nchembio0607-304