The localization of FOXO3a to Lewy bodies and Lewy neurites in PD and LBD indicates that FOXO3a is a potential component of Lewy bodies. While Lewy bodies are known also to be comprised of α-synuclein and ubiquitin  and occur in a variety of clinical disease states [7, 22–24], the mechanism of α-synuclein accumulation in the Lewy body and its role in disease is poorly understood . The finding of FOXO3a in intimate association with PD/LBD lesions suggests that LB and Lewy neurite formation encompasses more basic cellular pathophysiology than simple "gain of function" toxicity. Given the role of FOXO in such processes as phosphorylation, acetylation/deacetylation, ubiquitination, and protein-protein interactions , the potential of multiple hits cannot be discounted [26, 27]. In fact, FOXO3a has been shown to trigger the death of motoneurons in mice with the translocation from cytoplasm to nucleus , and a recent study also showed oxidative stress induces neuronal necrosis by activating FOXO3 .
Interestingly, however, several lines of evidence now indicate that α-synuclein accumulation is fundamentally protective [30, 31]. In our own studies, α-synuclein aggregation occurs in concert with microtubule polymerization and that an aggregate, once formed, is cytoprotective response against noxious stimuli [32, 33]. This is compatible with the once controversial concept that neurodegenerative disease lesions are markers of pathogenic disease response rather than indicators of etiology [34, 35]
Oxidative stress is believed to be an important factor in cell death induction and considerable evidence has accumulated that oxidative stress is involved in the pathogenesis of PD and α-synuclein aggregation [36–38]. As a transcription factor, it is necessary for FOXO3a to locate in nucleus to play its cell death-inducing role. In the present study, the high level expression of FOXO3a protein in an inclusion body in the neuronal cytoplasm suggests that FOXO3a may not reach the nucleus (e.g., to affect its known function in the apoptotic pathway). This finding adds further evidence to the notion that Lewy bodies may protect affected neurons from death and furthers the notion that profound alterations in cytoplasmic-nuclear trafficking are a key element of the neurodegenerative process [39, 40]. The finding of the specific isoform FOXO3a in neurodegenerative disease as presented in this work, as well as its role in attenuating amyloid-like pathology in mouse models , clearly supports the investigation of the other members of the FOXO family transcription factor in aging and disease.
14-3-3 is a family of dimeric proteins that can modulate interaction between proteins and they are involved in cell signaling, regulation of cell cycle progression, intracellular trafficking/targeting, cytoskeletal structure and transcription [42, 43]. In previous studies, phosphorylated FOXO3a has been shown to bind to 14-3-3 protein, causing cytoplasmic retention of phosphorylated FOXO3 and inhibition of FOXO3-induced transcriptional activation . Interestingly, 14-3-3 protein has also been localized to Lewy bodies . Therefore, while the mechanism of accumulation of FOXO3a in Lewy bodies awaits further study, a direct interaction between FOXO3a and 14-3-3 protein remains a distinct possibility. Since α-synuclein shares physical and functional homology with 14-3-3 proteins , it is reasonable to speculate that FOXO3a, α-synuclein, and 14-3-3 protein may form a complex, preventing the dephosphorylation and translocation of FOXO3a, and promote cell survival. This potential protein interaction is the subject of ongoing studies in our laboratory.