Neuronal autophagy, α-synuclein clearance, and LRRK2 regulation: a lost equilibrium in parkinsonian brain.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Friedman et al. The two major cellular mechanisms responsible for clearance of proteins and organelles are the ubiquitin–proteasome system (UPS) and the autophagy–lyso-somal pathway (ALP). Whereas UPS degrades most short-lived soluble proteins, the ALP is involved in degradation of long-lived protein aggregates and organ-elles. Of the two, autophagy is particularly important for maintaining cellular homeo-stasis in differentiated, postmitotic neuronal cells. However, despite their different contribution to protein degradation, both UPS and ALP have been implicated in various pathological conditions, including neuro-degenerative diseases. One disease in which dysfunctions of the UPS and ALP have been suggested to play an important role is Parkinson's disease (PD). Pathologically, PD is characterized by progressive neurodegeneration of dopaminergic (DA) neurons in the sub-stantia nigra pars compacta (SNpc) and by the presence of intracellular protein-aceous inclusions (Lewy bodies) in surviving neurons. ␣-Synuclein (␣-syn), a presynaptic protein prone to misfolding and aggregation, is the major component of Lewy bodies. However, larger aggregates and fibrils found in Lewy bodies are believed to be less toxic to neurons compared with ␣-syn oligomeric species, which occur earlier in ␣-syn aggregation (Winner et al., 2011). Three-point mutations in the gene encoding ␣-syn (SNCA), as well as SNCA multiplications, are linked to dominantly inherited forms of PD. Furthermore, overexpression of wild-type human ␣-syn or its pathological mutants can induce features of parkinsonism in animal models. Because defects of protein degradation pathways have been observed in the presence of abnormal ␣-syn expression, recent studies have investigated the mech-anism(s) of ␣-syn degradation under normal and pathological conditions (for review, see Ebrahimi-Fakhari et al., 2012). Overall, the emerging picture is that both UPS and ALP are involved in ␣-syn clearance , and contribution of each seems to depend on the aggregation state of the protein. More in detail, most of the in vivo studies have shown that the UPS system seems to be responsible for ␣-syn degradation under physiological conditions, whereas in pathological contexts, when the level of ␣-syn is increased, the au-tophagy pathway is activated. A second protein mutated in cases of dominantly inherited PD is leucine-rich repeat kinase 2 (LRRK2), and …