FOXO3 determines the accumulation of α-synuclein and controls the fate of dopaminergic neurons in the substantia nigra

Abstract

Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of α-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons using viral vectors and explore how this determinant of longevity impacts on neuronal fate in normal and diseased conditions. We find that dopaminergic neurons are particularly vulnerable to changes in FOXO3 activity in the substantia nigra. While constitutive activation has proapoptotic effects leading to neuronal loss, inhibition of FOXO-mediated transcription by a dominant-negative competitor causes oxidative damage and is detrimental at high vector dose. To address the role of FOXO3 in PD, we modulate its activity in dopaminergic neurons overexpressing human α-synuclein. In this pathogenic condition, we find that FOXO inhibition has protective effects, suggesting that this transcription factor ultimately contributes to neuronal cell death. Nevertheless, mild FOXO3 activity also protects nigral neurons against the accumulation of human α-synuclein, albeit to a lesser extent. FOXO3 reduces the amount of α-synuclein present in the soluble protein fraction and promotes the coalescence of dense proteinase K-resistant aggregates, with an accumulation of autophagic vacuoles containing lipofuscin. Consistent with these in vivo observations, we find that FOXO3 controls autophagic flux in neuronal cells. Altogether, these results point to FOXO3 as an important determinant of neuronal survival in the substantia nigra, which may oppose α-synuclein accumulation and proteotoxicity.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Remarkably, Foxos have also been implicated in the autophagy and mitophagy of neurons. FOXO3 has been shown to control the accumulation of human α‐synuclein, a protein known to participate in the development of Parkinson's disease (Pino et al ., 2014). Mild FOXO3 activity protects nigral neurons against the accumulation of human α‐synuclein by promoting its degradation.…”

FOXO transcription factors: key regulators of cellular quality control

“…Regulation of autophagy and mitophagy by FOXO transcription factors has also been observed in mammalian neurons [31, 48], which may have ramifications for neurodegenerative diseases. Similar to other cell types, several autophagy genes are activated in neurons in response to FOXO1 nuclear localization, including Bnip3, Beclin1 and Atg5 (Figure 1A) [31].…”

FOXO in Neural Cells and Diseases of the Nervous System

“…FOXO3’s pro-apoptotic and survival activities have been evaluated in a Parkinson’s disease (PD) model by overexpression of wild-type, constitutively active and dominant-negative constructs in dopaminergic neurons of the substantia nigra (Pino et al, 2014). In agreement with many findings in other neuronal types overexpression of constitutively active FOXO3 induced acute apoptosis in DA neurons.…”