title: Senescence marker protein 30 deficiency increases Parkinson's pathology by impairing astrocyte activation.
abstract: Senescence marker protein 30 (SMP30) was recently identified as gluconolactonase, which is involved in vitamin C (VC) biosynthesis. Therefore, the antioxidant property of SMP30 is thought to be mediated by its gluconolactonase function. However, pathologic effects of SMP30 deficiency independent of VC biosynthesis have not been studied in models of neurodegenerative diseases. In the present study, we evaluated the effect of SMP30 deficiency on Parkinson's disease (PD) in SMP30 knockout (KO) mice. Wild type and SMP30 KO mice supplemented with VC were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results showed that MPTP-induced dopaminergic neuronal loss and motor function impairment were more significant in the SMP30 KO mice. Reactive oxygen species generation and microglia activation were higher in MPTP-treated SMP30 KO mice. However, SMP30 deficiency mitigated MPTP-induced astrocyte activation and glia-derived neurotrophic factor production. Cultures of astrocytes recovered from wild type and SMP30 KO mice revealed that SMP30 deficiency abolished 1-methyl-4-phenyl-pyridinium-induced astroglial activation by blocking the extracellular signal-regulated kinase pathway. Taken together, our findings demonstrate for the first time that SMP30 deficiency increases the severity of PD and suggest a beneficial role of SMP30 in protective astrocyte activation in response to neurodegeneration. The present study shows that modulation of astrocytic SMP30 can be a promising target for treating PD.
authors.affiliation: College of Pharmacy and Research Institute for Drug Development, Longevity Life Science and Technology Institutes, Pusan National University, Busan, South Korea.
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Tae Gen
authors.initials: TG
authors.lastname: Son
authors.forename: Hee Ra
authors.initials: HR
authors.lastname: Park
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
authors.forename: Akihito
authors.initials: A
authors.lastname: Ishigami
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002470:Cell Survival; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology*
chemical_list: D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C513324:Rgn protein, mouse