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, 125 (1), 65-74

Autophagy and Neurodegeneration


Autophagy and Neurodegeneration

Rebecca A Frake et al. J Clin Invest.


Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.


Figure 2
Figure 2. Points of action of autophagy-upregulating agents.
This simplified schematic shows some of the pathways known to control autophagy and indicates where drugs and other agents act that are used to upregulate autophagy. In the interest of clarity, not all interactions of these pathways are shown. Both the mTOR-dependent and mTOR-independent pathways negatively regulate the autophagic process, and inhibition of these pathways will lead to an upregulation of autophagy. In the case of mTOR, this may occur through relieving the inhibition of the ULK1 complex, which is a positive regulator of autophagy. In the case of mTOR-independent regulation, the points of interaction between many agents in this category and the autophagy machinery are not known.
Figure 1
Figure 1. Intersections of the autophagic pathway and neurodegenerative diseases.
This schematic shows the progression through the autophagic pathway from formation of the autophagosome to fusion with the lysosome. Red text highlights points of compromise in the pathway that have been demonstrated in neurodegenerative disease, along with examples of causes of this compromise.

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