Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease

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.

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…61 However, little is currently known about the specific function of PLIN3 in beta cells. 144 There currently is little information regarding the role of PLIN4 in beta cells. PLIN4 has three times larger molecular weight compared with other PLINs, and the least studied among PLINs in nonbeta cells.…”

“…143 Recently, PLIN4 was found to inhibit mitophagy in a neuroblastoma cell line. 144 There currently is little information regarding the role of PLIN4 in beta cells. Of note, the expression of PLIN4 in beta cells and pancreatic islets is very low (Fig.…”

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

“…It is upregulated during systemic inflammation (Kang et al 2017) and has been found to be elevated in the brains of AD patients (Naudé et al 2012). Plin4 is often associated with triacylglycerol metabolism and is involved in the biogenesis of lipid droplets in pathological degeneration (Han et al 2018). The PolyI:C model shows a strong and specific rise in lipid droplets density accompanied by an increase in Lcn2 protein levels in neurons and glia, which confirms the metabolic and inflammatory disbalance in response to systemic immune challenge.…”

“…5F). (II) On the other hand, genes related to neuroinflammation such as the lipiddroplet dependent gene (Plin4; Perilipin 4) (Han et al 2018), pro-inflammatory genes (H2-Aa; Immunohistocompatibility-complex) (Van Hove et al 2019) and acute-phase proteins regulating to the inflammatory response (Lcn2; Lipocalin-2) (Dekens et al 2020) are upregulated in aging PP mice, starting from 9 months (Fig. 5G).…”

A non-canonical lipid droplet metabolism regulates the conversion of alpha-Synuclein to proteolytic resistant forms in neurons of aDrosophilamodel of Parkinson disease

“…Several studies have reported that expression of human Syn dysregulates TG metabolism and LD homeostasis in cellular and rodent models of PD (Cole et al, 2002;Fanning et al, 2019;Han et al, 2018;Outeiro and Lindquist, 2003;Sánchez Campos et al, 2018). As noted above, LD homeostasis crucially relies on peridroplet proteins.…”