Abstract
Epidemiological studies have shown that both lipid metabolism disorder and mitochondrial dysfunction are correlated with the pathogenesis of neurodegenerative diseases (NDDs), including Parkinson’s disease (PD). Emerging evidence suggests that deposition of intracellular lipid droplets (LDs) participates in lipotoxicity and precedes neurodegeneration. Perilipin family members were recognized to facilitate LD movement and cellular signaling interactions. However, the direct interaction between Perilipin-regulated LD deposition and mitochondrial dysfunction in dopaminergic (DA) neurons remains obscure. Here, we demonstrate a novel type of lipid dysregulation involved in PD progression as evidenced by upregulated expression of Plin4 (a coating protein and regulator of LDs), and increased intracellular LD deposition that correlated with the loss of TH-ir (Tyrosine hydroxylase-immunoreactive) neurons in the MPTP/p-induced PD model mouse mesencephalon. Further, in vitro experiments showed that inhibition of LD storage by downregulating Plin4 promoted survival of SH-SY5Y cells. Mechanistically, reduced LD storage restored autophagy, leading to alleviation of mitochondrial damage, which in turn promoted cell survival. Moreover, the parkin-poly-Ub-p62 pathway was involved in this Plin4/LD-induced inhibition of mitophagy. These findings were further confirmed in primary cultures of DA-nergic neurons, in which autophagy inhibitor treatment significantly countermanded the ameliorations conferred by Plin4 silencing. Collectively, these experiments demonstrate that a dysfunctional Plin4/LD/mitophagy axis is involved in PD pathology and suggest Plin4-LDs as a potential biomarker as well as therapeutic strategy for PD.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), affecting 2–3% of the population over the age of 65 (Poewe et al, 2017)
To determine whether lipid droplets (LDs) formation occurs in mammalian models and participates in the pathogenesis of PD, we generated the MPTP neurotoxin-induced PD mouse model for chronic mitochondrial dysfunction-associated loss of DA neurons using a previously described protocol (Lu et al, 2014)
LDs are identifiable in Figure 1D, similar to results reported previously (Singh et al, 2009), showing round, light-density structures not limited by a lipid bilayer membrane (Middle frame, red arrow), with homogenous amorphous content that was increased in both size and amount in response to MPTP/p stimuli
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the preferential loss of dopaminergic neurons in the SNpc, affecting 2–3% of the population over the age of 65 (Poewe et al, 2017). The exact etiology and natural course of PD have yet to be fully clarified but involve dysfunction of numerous system-level processes, including mitochondrial function, calcium and dopamine homeostasis, neuroinflammation, and autophagy (Athauda and Foltynie, 2015; Ascherio and Schwarzschild, 2016; Poewe et al, 2017), highlighting the predominant role of mitochondrial dysfunction (Ryan et al, 2015; Onyango et al, 2017). Genome-wide association studies (GWAS) have identified many of the PD-associated genes such as PINK, PARKIN and DJ-1, which have been shown to either directly or indirectly play roles in mitochondrial homeostasis or mitophagy (Dawson and Dawson, 2017; Onyango et al, 2017). Recent studies have indicated that abolished mitophagymediated clearance of mtDNA and mtROS rendered impaired mitochondria as activators of the NLRP3 inflammasome to trigger neuroinflammation and promote DA neuronal loss (Yan et al, 2015; Zhong et al, 2016). The role that regulation of mitophagy plays in the pathogenesis of PD needs further exploration
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