Abstract
Accumulating evidence suggests a crucial role for the unfolded protein response (UPR) in Parkinson’s disease (PD). In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P) injection, which causes severe and persistent degeneration of dopaminergic neurons. Enhanced activation of the UPR branches, including ATF6α and PERK/eIF2α/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6α gene accelerated neuronal degeneration and ubiquitin accumulation relatively early in the MPTP/P injection course. Surprisingly, astroglial activation was strongly suppressed, and production of the brain-derived neurotrophic factor (BDNF) and anti-oxidative genes, such as heme oxygenase-1 (HO-1) and xCT, in astrocytes were reduced in ATF6α −/− mice after MPTP/P injections. Decreased BDNF expression in ATF6α −/− mice was associated with decreased expression of GRP78, an ATF6α-dependent molecular chaperone in the ER. Decreased HO-1 and xCT levels were associated with decreased expression of the ATF4-dependent pro-apoptotic gene CHOP. Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4′-pentamethoxyflavone; IN19) into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. These results suggest that the UPR is activated in a mouse model of chronic MPTP/P injection, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disease pathologically characterized by the selective loss of nigrostriatal dopaminergic neurons and the presence of protein aggregates, known as Lewy bodies [1]
unfolded protein response (UPR) in the Chronic MPTP with probenecid (MPTP/P) Injection PD Model When MPTP/P was injected into C57BL/6 wild-type mice, the number of TH-positive dopaminergic neurons in the SNpc and the intensity of TH in the caudate putamen (CPu) gradually decreased (Fig. 1 A I, Fig. 2 A I, inclusion bodies (II))
Of the 3 UPR branches, the activating transcription factor 6a (ATF6a) and PERK/eIF2a/activating transcription factor 4 (ATF4) pathways were preferentially activated after MPTP/P injections (Fig. 1 B)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disease pathologically characterized by the selective loss of nigrostriatal dopaminergic neurons and the presence of protein aggregates, known as Lewy bodies [1]. MPTP causes oxidative stress and energy depletion because of impaired mitochondrial function, recent studies suggest that MPTP causes endoplasmic reticulum (ER) stress, a type of intracellular stress that is characterized by the accumulation of unfolded proteins in the ER. Eukaryotic cells respond to ER stress by activating a set of pathways known as the unfolded protein response (UPR) [6]. A recent report demonstrated that MPP+-associated oxidative stress enhanced the interaction between phosphorylated p38 mitogen-activated protein kinase (p38MAPK) and ATF6a, causing increased transcriptional activity of ATF6a [12]. These findings suggest an important communication between the oxidative stress response and the UPR in PD pathogenesis
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