Oxyphylla a promotes degradation of α-synuclein for neuroprotection via activation of immunoproteasome
Zhou,Hefeng1; Li,Shengnan1; Li,Chuwen1; Yang,Xuanjun1,2; Li,Haitao1; Zhong,Hanbing2; Lu,Jia Hong1; Lee,Simon Ming Yuen1
Source PublicationAging and Disease
AbstractParkinson's disease (PD), the second most common neurodegenerative disorder, is neuropathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies in surviving neurons. α-synuclein (α-syn) is the major component of Lewy bodies and its deposition in neurons is critical pathological event in the pathogenesis of PD. Herein, we reported that Oxyphylla A, a novel lead compound from the fruit of Alpinia oxyphylla, significantly promoted α-syn degradation in a cellular PD model. When exploring the molecular pathways, we found that Oxyphylla A promoted α-syn degradation in a ubiquitin proteasome system (UPS)-dependent and autophagy-independent manner. We further confirmed that Oxyphylla A enhanced UPS activity by upregulating 20S subunit PSMB8 expression. A mechanism study revealed that Oxyphylla A activated the PKA/Akt/mTOR pathway to trigger PSMB8 expression and enhance UPS activity. Finally, we illustrated that Oxyphylla A alleviated the accumulation of both Triton-soluble and Triton-insoluble forms of α-syn and protected against α-syn-induced neurotoxicity in A53T α-syn transgenic mice. These findings suggest that the activation of UPS, via small molecular UPS enhancers including Oxyphylla A, may be a therapeutic strategy for intervention against PD and related diseases.
KeywordDegradation Neuroprotection Parkinson's disease Proteasome α-synuclein
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Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Macao
2.Department of Biology,South University of Science and Technology,Shenzhen,China
First Author AffilicationInstitute of Chinese Medical Sciences
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GB/T 7714
Zhou,Hefeng,Li,Shengnan,Li,Chuwen,et al. Oxyphylla a promotes degradation of α-synuclein for neuroprotection via activation of immunoproteasome[J]. Aging and Disease,2020,11(3):559-574.
APA Zhou,Hefeng.,Li,Shengnan.,Li,Chuwen.,Yang,Xuanjun.,Li,Haitao.,...&Lee,Simon Ming Yuen.(2020).Oxyphylla a promotes degradation of α-synuclein for neuroprotection via activation of immunoproteasome.Aging and Disease,11(3),559-574.
MLA Zhou,Hefeng,et al."Oxyphylla a promotes degradation of α-synuclein for neuroprotection via activation of immunoproteasome".Aging and Disease 11.3(2020):559-574.
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