Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's disease

Abstract

Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas α-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of α-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and α-synuclein may be key.

Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

“…In line with some studies suggesting a protective role for ASYN accumulation, transcription factor, FOXO3a, was also detected in LBs and LNs in PD and DLB [306]. Intriguingly, the amount of ASYN in neurons seems to represent a key element in determining its tendency towards opposing roles, with lower levels being crucial for cell protection against specific insults and high levels promoting harmful effects [266].…”

Engulfment adaptor phosphotyrosine-binding-domain-containing 1 (GULP1) is a nucleocytoplasmic shuttling protein and is transactivationally active together with low-density lipoprotein receptor-related protein 1 (LRP1)

“…Our data underline the important role of adaptor proteins in AD and are in line with findings implicating defects in the cell’s nuclear trafficking in other neurodegenerative diseases, including RNA-binding protein fused in sarcoma (FUS) in frontotemporal dementia (FTLD) and amylotrophic lateral sclerosis (ALS) [37], altered transcription factor nuclear trafficking in neurodegeneration[38], TDP-43 in ALS/FTLD and FOXO3a in Lewy-Body dementia [39]. …”

Enhanced Phosphatidylinositol 3-kinase (PI3K)/Akt Signaling Has Pleiotropic Targets in Hippocampal Neurons Exposed to Iron-induced Oxidative Stress

“…Although the triple-phosphorylated form is exported from the nucleus and retained in the cytoplasm in a Crm-1-and 14-3-3-dependent manner, the nonphosphorylated form resides in the nucleus and is capable of transcribing target apoptotic genes (12). Thus, FoxO transcriptional activity is essential in programmed cell death during development but has also been implicated in the initiation of apoptosis during neuronal injury, as in the case of neurodegenerative disorders in the mature nervous system (13,14).…”