Medicine by Alexandros G. Sfakianakis: Autophagy as a Therapeutic Target: The Double-edged Sword

Τρίτη 7 Νοεμβρίου 2017

Autophagy as a Therapeutic Target: The Double-edged Sword

By Christina Towers, PhD

Autophagy is an important cellular process that facilitates the degradation of damaged cytoplasmic material and toxic protein aggregates. Its role in neuronal function is apparent by the neurodegenerative phenotypes observed in autophagy deficient genetic mouse models. Mice with neuron-specific knock out of the core autophagy protein, ATG7, are viable but most go on to develop behavioral defects and eventually massive neuronal loss in the cerebral corticies¹.

But perhaps the most causative links between autophagy and neurological functioning have been observed in animal models of progressive neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease. Each of these devastating diseases is characterized by a build-up of toxic protein aggregates: β-amyloid peptides and Tau proteins in the case of Alzheimer's, α-synuclein or lewy bodies in Parkinson's, or polyQ-containing proteins transcribed from a mutant HTT gene in Huntington's disease². The inherent function of autophagy in all cells is to degrade toxic proteins, and neurons in particular rely on this process to maintain homeostasis and prevent toxic accumulations of the above mentioned pathological proteins. Specifically, in Huntington's disease, substandard autophagosomes are formed that are devoid of contents resulting in a build-up of mutant HTT proteins³. Additionally, mutant HTT can interfere with autophagosome-lysosome fusion, a critical step in maintaining autophagosome degradation⁴.

brain graphic

In Alzheimer's disease, the hippocampus is the first brain region affected, leading to loss of short-term memory. Huntington's disease affects first the basal ganglia leading to defective motor control. Finally, Parkinson's disease primarily affects substantia nigra dopaminergic neurons and resulting in uncontrolled-body movements.

There has been a large effort to discover autophagy inducing compounds that could be used to combat these deadly diseases. These compounds include mTOR inhibitors like Rapamycin analogs, resveratrol, and metformin as well as natural products like trehalose and curcumin. A number of these compounds are moving into pre-clinical rodent models and even phase I clinical trials for nuerodegenerative diseases². An unfortunate caveat to these experiments, however, is that all of these drugs can have autophagy independent targets, making any successful results difficult to interpret as strictly a result of autophagy inhibition.

Perhaps the most interesting question these studies beg is what on-target neurological side effects can be anticipated from targeted autophagy inhibition in cancer, a disease where autophagy plays a pro-tumorigenic role. There are currently over 50 clinical trials attempting to inhibit autophagy with the lysosomal inhibitor, chloroquine, across multiple tumor types. Thus far neurological side effects have not have been observed, but all of these studies are either still in progress or just recently concluded, without the ability to track any long-term side effects in these patients. Pre-clinical mouse studies with induced systemic loss of autophagy in a developed tumor showed a complete regression of the lesions, however, the mice developed a number of adverse side effects including neurodegeneration⁵. Importantly, these studies do suggest that a therapeutic window may exist where incomplete autophagy inhibition (it is unlikely that any pharmacological compound will be 100% efficient) for a short period of time may be sufficient to reduce tumor growth without neurological side effects. Nonetheless, these potential issues need to be addressed over the course of ongoing clinical trials, as do the reverse – the effects of autophagy induction to treat neurodegeneration and on-target side effects on cancer incidence and progression.

New Alzheimer's Poster

References

Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884, doi:10.1038/nature04723 (2006).
Towers, C. G. & Thorburn, A. Therapeutic Targeting of Autophagy. EBioMedicine, doi:10.1016/j.ebiom.2016.10.034 (2016).
Martinez-Vicente, M. et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat Neurosci 13, 567-576, doi:10.1038/nn.2528 (2010).
Wong, Y. C. & Holzbaur, E. L. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci 34, 1293-1305, doi:10.1523/JNEUROSCI.1870-13.2014 (2014).
Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 4, 914-927, doi:10.1158/2159-8290.CD-14-0363 (2014).