Targeting macroautophagy to combat neurodegenerative disease: strategies and considerations

Upon demonstration that basal macroautophagy plays an essential role in maintaining protein homeostasis in the mammalian CNS, there has been excitement around modulating this form of autophagy as a therapeutic strategy to combat neurodegenerative disease. Nonetheless, the initial genetic studies that spawned this excitement did little to reveal the complex physiology of autophagy regulation in neural cells, or the predicament of compartment-specific events upon which these cells rely. Pursuit of therapeutic strategies further highlighted how this intricacy extends across the different organs of the body, raising question as to how we may harness the power of macroautophagy for good while minimizing the bad. Fortunately, since these early studies, the field has made significant gains toward understanding the molecular, cellular and physiological basis of macroautophagy. Together with technological advances, they have refueled the exploration into how this powerful pathway may provide the much-needed therapeutic advances for these yet untreatable diseases. In this review, we will contextualize the insights gained over the last decade with the traditional and novel strategies that have been explored to combat disease-associated events such as abnormal protein accumulation. In addition, we will discuss key considerations and strategies that can influence how a therapeutic approach might be designed.