Maintaining autophagic balance: A role for brakes

Dysregulation of macroautophagy has been implicated in multiple disease processes, from neurodegeneration to neoplasia. Basal autophagy is essential for maintaining cellular health, particularly in post-mitotic cells such as neurons, and autophagy is induced in response to a wide array of physiological and pathological stresses. Clearly, maintaining a finely tuned balance between protein/organelle degradation and reparative biosynthesis is crucial to cellular and organismic health. Moreover, autophagy induction that outstrips cellular capacities for autophagosome maturation/clearance places neurons under additional autophagic stress. While much has been learned within the last ten years about processes necessary for autophagy to proceed, our understanding of braking mechanisms to reduce or slow the degree of autophagy induction is just beginning to emerge. Mechanisms applicable to both canonical nucleation and Beclin 1-independent autophagy are reviewed in context with the pathological consequences of insufficient negative regulation in models of acute neuronal injury and Parkinson’s disease.