Cleaning up epilepsy and neurodegeneration: the role of autophagy in epileptogenesis.

Commentary Autophagy, literally meaning " self-eating, " is an evolutionarily conserved housekeeping function of most cells. Autophagy involves sequestration, removal, and degradation of cellular components by lysosomes. Three subtypes of autophagy have been described—macroautophagy, microautophagy, and chaperone-mediated autophagy—which differ in their mechanisms of delivery of substrates to the lysosome for degradation. Macro-autophagy (henceforth referred to as autophagy) represents the primary, best characterized form and involves several steps. First, an initial membrane apparatus forms within the cytoplasm as a site for assembly and collection of cellular debris. The structure then elongates and creates a double membrane, forming a vacu-olar autophagosome, which is then transported by microtubules toward microtubule-organizing centers where lysosomes are located. Finally, fusion of the autophagosome and lysosome allows the contents to be degraded by lysosomal enzymes. Autophagy plays a central role in many important physiological and pathological processes (1). First of all, autophagy helps remove old or dysfunctional cellular components, such as misfolded proteins or damaged organelles. Without autophagic clearance, the accumulation of intracellular debris could result in release of harmful reactive oxidation species into the cytoplasm or have other toxic effects on cells. As autophagic mechanisms are closely coupled to related mechanisms of apoptosis, autoph-agy is integrally linked to decisions about cellular fate, survival, and death. Autophagy is also involved in the body's response to environmental stressors, such as trauma, infection, inflammation , and starvation. For example, under catabolic states of nutrient deprivation, autophagy adopts a critical metabolic function in providing key nutrients, such as amino acids, derived from degradation of autophagic substrates. Recently, autophagy has also been implicated in basic brain development and function, such as synaptic transmission and plasticity that may relate to learning and memory (2, 3). Dysfunction of autophagic mechanisms has been associated with a variety of disease states, including neurodegenera-tive disorders (4, 5). Several classic neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer disease are characterized pathologically by accumulation of abnormal protein aggregates or other cytoplasmic inclusions. Although the pathophysiological significance of these protein aggregates is still debated, a prominent hypothesis is that these aggregates have toxic effects that cause neuronal degenera-tion. A defect in autophagic mechanisms could contribute to accumulation of protein aggregates in these neurodegen-erative diseases. For example, in cellular and mouse models of Huntington disease, autophagic vacuoles demonstrate inefficient recognition and accumulation of targeted cargo, which might result in toxic aggregates of huntingtin protein (6). Conversely, from a therapeutic …