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Cited by 42Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingAutophagy in Disease and Therapy

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Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation

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Han, Xiaojuan, Liu, Yuan, Dai, Yan, Xu, Tianshu, Hu, Qinghui, Yi, Xiaolan, Rui, Liangyou, Hu, Gang, Hu, Jun·2022·Redox Biology
DOI 10.1016/j.redox.2022.102308PMC PMC8987406
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Abstract

The incidence of Parkinson's disease (PD) has increased tremendously, especially in the aged population and people with metabolic dysfunction; however, its underlying molecular mechanisms remain unclear. SH2B1, an intracellular adaptor protein, contributes to the signal transduction of several receptor tyrosine kinases and exerts beneficial metabolic effects for body weight regulation; however, whether SH2B1 plays a major role in pathological neurodegeneration in PD has not yet been investigated. This study aimed to investigate the effects of SH2B1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced PD mice with Sh2b1 deficiency or neuron-specific Sh2b1 overexpression. Cellular and molecular mechanisms were elucidated using human dopaminergic neuron SH-SY5Y cells analysed. We found that SH2B1 expression was confirmed to be downregulated in the blood samples of PD patients and in the brains of mice with MPTP-induced chronic PD. Sh2b1 deficiency caused marked exacerbation of behavioural defects and increased neuronal apoptosis in MPTP-treated mice, whereas restoration of neuron-specific Sh2b1 expression significantly reversed these effects. Similar results were observed in MPP + -treated SH-SY5Y cells. Mechanistically, upon binding to heat shock cognate 70 (HSC70), SH2B1 promotes HSC70-related recognition and PLIN4 lysosomal translocation and degradation, thus suppressing lipid peroxidation stress in the brains of PD mice. Adeno-associated virus-mediated rescue of neuronal HSC70 expression functionally alleviated the neuropathology of PD in wild-type but not in Sh2b1-deficient mice. This is the first study to examine the molecular underpinnings of SH2B1 against MPTP-induced neurodegeneration through cell autonomous promotion of neuronal survival in an in vivo PD model. Our findings reveal that SH2B1 antagonizes neurodegenerative pathology in PD via the SH2B1–HSC70–PLIN4 axis.

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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 [31]

    The Results section on SH2B1 deficiency reports increased PLIN4 in the midbrains of MPTP-treated mice. Another Results section refers to a PLIN4/LD/mitophagy axis, and the Discussion describes PLIN4 degradation through HSC70, but neither establishes that elevated PLIN4 disrupts mitophagy or impairs chaperone-mediated autophagy. The Discussion instead says the detailed regulation of the CMA–lysosomal pathway remains unclear. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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Metadata

Authors
Han, X., Liu, Y., Dai, Y., Xu, T., Hu, Q., Yi, X., Rui, L., Hu, G., & Hu, J.
Affiliations
  • Nanjing University of Chinese Medicine (CN)
  • Jiangsu Province Hospital (CN)
  • University of Michigan (US)
Corresponding author
  • Hu, Gang
  • Hu, Jun
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2022-06
Volume
52
Pages
102308
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2022.102308
PMC
PMC8987406
OpenAlex
W4220974683
Cited by
42
References
1
Citations by year
2026: 17 · 2025: 14 · 2024: 8 · 2023: 2 · 2022: 1
FWCI
3.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Natural Science Foundation of Jiangsu Province (BK20190120)
  • National Natural Science Foundation of China (81672218, 81903587)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
SH2B1, Parkinson's disease, MPTP, neuronal apoptosis, Hsc70, lipid peroxidation, dopaminergic neurons, neurodegeneration, lysosomal translocation, MPP+, SH-SY5Y cells, neuroprotection
MeSH terms
Perilipin-4, Aged, Animals, Disease Models, Animal, Humans, Mice, Inbred C57BL, Parkinson Disease, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Apoptosis, Adaptor Proteins, Signal Transducing, Mice, Dopaminergic Neurons

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