The Role of Autophagy on the Survival of Dopamine Neurons

Ciro      Isidoro; Francesca      Biagioni; Filippo   Sean   Giorgi; Federica      Fulceri; Antonio      Paparelli; Francesco      Fornai

Abstract

Autophagy is the mechanism through which cells degrade oxidized membranes-organelles and mis/unfolded proteins, in this latter function cooperating with the ubiquitin-proteasome system (UP system). Although autophagy has been known for a long time, its involvement in the pathogenesis of neurodegenerative diseases has been investigated only recently. The most fascinating data are very recent and show an impressive connection between proteins that are mutated in different forms of familial Parkinsons Disease (PD) and the critical role that these proteins play in the physiology of the Autophagy (ATG) pathway. This evidence is supported by neuropathological data showing at the ultrastructural level, the occurrence of an altered ATG in the dopamine (DA) neurons of the Substantia Nigra of patients affected by PD. Accordingly, by using experimental models of PD the involvement of ATG is documented as well. In particular, administration of the DA neurotoxin methamphetamine produces damage to DA-containing cells which is exacerbated and results in neuronal cell death when the ATG pathway is inhibited, thus confirming ATG as a critical pathway for the survival of DA neurons. In the present manuscript, after describing the general molecular and cellular features of ATG, we give a short overview of the most relevant aspects concerning the involvement of ATG in the pathogenesis of PD. We further propose that the ATG and the UP systems might converge in the formation of a so-called “autophagoproteasome” which might represent an early ultrastructure witnessing the presence of an ongoing degeneration within DA cells.

Keywords: Parkinson's Disease, ATG, alpha-synuclein, dopamine, proteasome, autophagoproteasome, methamphetamine, lysosome