Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy

Background:Progressive accumulation ofα-synuclein is a key step in the pathological development of Parkinson’s disease.Impaired protein degradation and increased levels ofα-synuclein may trigger a pathological aggregation in vitro and in vivo.The chaperone-mediated autophagy(CMA)pathway is involved in the intracellular degradation processes ofα-synuclein.Dysfunction of the CMA pathway impairsα-synuclein degradation and causes cytotoxicity.Results:In the present study,we investigated the effects on the CMA pathway andα-synuclein aggregation using bioactive ingredients(Dihydromyricetin(DHM)and Salvianolic acid B(Sal B))extracted from natural medicinal plants.In both cell-free and cellular models ofα-synuclein aggregation,after administration of DHM and Sal B,we observed significant inhibition ofα-synuclein accumulation and aggregation.Cells were co-transfected with a Cterminal modifiedα-synuclein(SynT)and synphilin-1,and then treated with DHM(10μM)and Sal B(50μM)16 hours after transfection;levels ofα-synuclein aggregation decreased significantly(68%for DHM and 75%for Sal B).Concomitantly,we detected increased levels of LAMP-1(a marker of lysosomal homeostasis)and LAMP-2A(a key marker of CMA).Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A withα-synuclein inclusions after treatment with DHM and Sal B.We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo,along with decreased levels ofα-synuclein.Moreover,DHM and Sal B treatments exhibited anti-inflammatory activities,preventing astroglia-and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice.Conclusions:Our data indicate that DHM and Sal B are effective in modulatingα-synuclein accumulation and aggregate formation and augmenting activation of CMA,holding potential for the treatment of Parkinson’s disease.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson’s disease: a study in LRRK2 mutation carriers

Background Asymptomatic carriers of leucine-rich repeat kinase 2(LRRK2)gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease(PD).In this study,we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.Methods We measured the levels of CSF total-(t-),oligomeric(o-)and phosphorylated S129(pS129-)α-syn,total-tau(tTau),phosphorylated threonine 181 tau(pTau),amyloid-beta 40(Aβ-40),amyloid-beta-42(Aβ-42)and 40 inflammatory chemokines in symptomatic(n=23)and asymptomatic(n=51)LRRK2 mutation carriers,subjects with a clinical diagnosis of PD(n=60)and age-matched healthy controls(n=34).General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups.Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.Results Discriminant function analysis revealed low levels of CSF t-α-syn,high levels of CSF o-α-syn and TNF-αbest discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls.Assessing the discriminative power using receiver operating curve analysis,an area under the curve>0.80 was generated.Conclusions The current study suggests that CSF t-,o-α-syn and TNF-αare candidate risk biomarkers for the detection of PD at the prodromal stage.Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’panel approach for an accurate and timely diagnosis of PD.