| Autor: |
Xiaojuan Han, Yuan Liu, Yan Dai, Tianshu Xu, Qinghui Hu, Xiaolan Yi, Liangyou Rui, Gang Hu, Jun Hu |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Redox Biology, Vol 52, Iss , Pp 102308- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2213-2317 |
| DOI: |
10.1016/j.redox.2022.102308 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
