Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson’s Disease
Open accessAbstract
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.
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PLIN4 is up-regulated in MPTP-induced mouse models of Parkinson's disease, with PLIN4 levels resulting in disrupted mitophagy as well as impaired chaperone-mediated autophagy.
“It is up-regulated in MPTP-induced mouse models of Parkinson’s disease (PD), with PLIN4 levels resulting in disrupted mitophagy as well as impaired chaperone-mediated autophagy, a mechanism of protein quality control [31, 32].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [32]
The Results section reports increased Plin4 expression in MPTP/p-treated mice and shows that Plin4 knockdown restored mitophagy in MPP+-treated SH-SY5Y cells. It does not report that PLIN4 impairs chaperone-mediated autophagy; the autophagy findings concern mitophagy. No page numbers are available in our copy. (LLM, conf=0.87)
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- Authors
- Han, X., Zhu, J., Zhang, X., Song, Q., Ding, J., Lu, M., Sun, S., & Hu, G.
- Affiliations
- Nanjing University of Chinese Medicine (CN)
- Nanjing Medical University (CN)
- Corresponding author
- Hu, Gang
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2018-06-18
- Volume
- 12
- Pages
- 397-397
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC6015897
- OpenAlex
- W2809346329
- Cited by
- 91
- References
- 40
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 10 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 14 · 2019: 3 · 2018: 1
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (No.81630099, No.81603091, No.81773706)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, lipid droplets, PLIN4, perilipin, mitophagy, dopaminergic neurons, autophagy, Parkin, p62, lipotoxicity, mitochondrial dysfunction, SH-SY5Y cells, tyrosine hydroxylase neurons, biomarkers
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