Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation
Xiaojuan Han,
Yuan Liu,
Yan Dai,
Tianshu Xu,
Qinghui Hu,
Xiaolan Yi,
Liangyou Rui,
Gang Hu,
Jun Hu
Affiliations
Xiaojuan Han
Department of Rheumatology and Immunology, Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China; Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China
Yuan Liu
Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China; Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Yan Dai
Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Tianshu Xu
Department of Rheumatology and Immunology, Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
Qinghui Hu
Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Xiaolan Yi
Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Liangyou Rui
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
Gang Hu
Department of Rheumatology and Immunology, Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China; Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Corresponding author. Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Guang Zhou Road 300, Nanjing, 210029, China.
Jun Hu
Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China; Corresponding author. Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Guang Zhou Road 300, Nanjing, 210029, China.
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.
