Abstract
BackgroundAbnormal accumulation and aggregation of microtubule associated proteins (MAPs) plays an important role in the pathogenesis of neurodegenerative diseases. Loss-of-function mutation of DJ-1/Park7 can cause early onset of PD. DJ-1, a molecular chaperone, can inhibit α-synuclein aggregation. Currently, little is known whether or not loss of function of DJ-1 contributes to abnormal MAPs aggregation in neurodegenerative disorders such as PD.ResultsWe presented evidence that DJ-1 could bind to microtubule associated protein1b Light Chain (MAP1b-LC). Overexpression of DJ-1 prevented MAP1b-LC aggregation in HEK293t and SH-SY5Y cells while DJ-1 knocking down (KD) enhanced MAP1b-LC aggregation in SH-SY5Y cells. The increase in insoluble MAP1b-LC was also observed in the DJ-1 null mice brain. Moreover, in the DJ-1 KD SH-SY5Y cells, overexpression of MAP1B-LC led to endoplasmic reticulum (ER) stress-induced apoptosis.ConclusionOur results suggest that DJ-1 acts as a molecular chaperone to inhibit MAP1B aggregation thus leading to neuronal apoptosis. Our study provides a novel insight into the mechanisms that underly the pathogenesis of Parkinson's disease (PD).
Highlights
Abnormal accumulation and aggregation of microtubule associated proteins (MAPs) plays an important role in the pathogenesis of neurodegenerative diseases
To study whether DJ-1 can interact with MAP1b-LC, GST-DJ-1 fusion protein and 6xHisMAP1b-LC were expressed in E. coli BL21 cells and purified respectively
The pull down assay showed that MAP1b-LC interacted with GST-DJ-1 but not with GST, suggesting that DJ-1 could bind to MAP1b directly in vitro (Figure 1A)
Summary
DJ-1 interacted with MAP1b-LC MAP1b-LC has been shown to be a potential DJ-1 binding protein [22]. Overexpression of DJ-1 decreased the insoluble MAP1b-LC fraction and inhibited the formation of MAP1b-LC aggregates when they were co-transfected into SH-SY5Y cells (Figure 2 C, D). The Western blot results showed an increase in insoluble MAP1b-LC in the DJ-1 KO mouse compared with that of the wild type (Figure 4F, G). Our results showed that phosphorylated eIF2a was much higher in MAP1b-transfected DJ-1 KD cells at 48 hrs after transfection compared with that in the scrambled control DJ-1 KD cells (Figure 7A). Salubrinal, the specific inhibitor of dephosphorylation of eIF2a [28] suppressed the MAP1b-LC induced apoptosis in DJ-1 KD SH-SY5Y cells (Figure 7C and 7D) Taken together, these results suggested that excessive MAP1b-LC aggregation caused by DJ-1 ablation may induce apoptosis in the ER stress dependent manner
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