ABST TRACT A sustained neuroinflam insult charac by massive microglia activation s been well mmatory cterized m has recognized as a major pathophysiologic contribut the progression neurodegenerative n cal tor to p of processes i nson's disea nterestingly, microglia c particularly Parkin ase (PD). In constitute a attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding minergic deg Recent studies pertainin nflammation s dopam generation. R ng to neuroi n in PD have generated tremendou enthusiasm because ?-synuclein (?Sy aggrega can serve as an endogenous antigen triggering yn) ates s a neurotoxicity by p potent micro ed proinflammatory response. Also, accumulating evidence provoking a oglia-mediat reveals that misfolded ?Syn spreads through a cell-to-cell transmission mechanism, contributing to the gation of ?S propa Syn patholog boring neuro al cells, possibly augmenting the progression of gy to neighb onal and glia PD. Despite these advance the fund neurobiological mechanisms regulat a es, damental ting sustained microgli activation and neuroinflamm casc during pathogenic ?Syn ggregate stimulation emain to be matory cades g ag re established. Thus, identificat of key targets contributing to microglia e tion o sustained activation could provid ac tial targets to progression o se. We recently obtained e potent o slow the p of the diseas d exciting new data showing that th voltage-gated pot nnel Kv1.3 is highly up n aggregated ?Syn-stimulated primary microglia tassium cha pregulated in and animal models of PD as well as in human PD ostmortem samples. mportantly, patch-clamp D, po s Im ophysiologic studies confirmed 3 electro cal that the observed Kv1.3 upregulation translates to increased Kv1. nel activity. A reliminary re st that a pro n chann Additional pr esults sugge oinflammatory kinase PKC? plays a role in ?Sy aggregate-induced Kv1.3 upr To further expand our novel preliminary results, we will systematically regulation. T pursue the following specific aims: (i) characteriz Kv1.3 pregulation and activation of pro-inflammatory ze up glia in anima f ?Syn aggr microg al models o regate-induc xicity, and define the role of Kv1.3 in microglia- ced neurotox ated neuroinflammation and augmentation of th igrostriatal d c media he neurodegenerative process in n dopaminergi ns in PD, (i the molecul upregulatio n neuro ii) unravel lar underpin 1.3 channel n in microglia during a nning of Kv1 ?Syn aggregate-induced ne Kv1.3 in e euroinflamma insult, and (iii) establish he role of mediating th atory e th m proinflammatory r the nigrostr minergic system during ?Syn prote response in riatal dopam in aggregation in animal ls of PD. We ultiple mode nd state-of-t l, model e will use m el systems a the-art biochemical, cellular, neurophysiologica histological and neurochemic approac to achieve these specific ms. Overall, we anticip that ou cal ches aim pate ur proposed studies will provid novel me insights into sustained microglia activation nd its role in de echanistic an neuroinflammator processes in PD dis progression and will offer novel thera ry s sease apeutic targe to curta ets ail neuroinflammator s in PD and o d neurodegenerative disorders. ry responses other related
Chronic ne euroinflamm cterized by p microglia activation resulting in substantial release mation charac persistent m of proinflammator and chemok ey pathologic feature of Parkinson's D). Given th ry cytokines kines is a ke s disease (P hat abnormal ?Synuc nic brain in process, to clein protein aggregates can trigge the chro nflammatory we propose n er w characterize the role of the potassium e major volt channel Kv1.3 during ?Syn aggregate-induced tage-gated inflammatory resp ll culture and odels of PD as well as in human PD brain samples. Our study ponses in ce d animal mo will provide new insights into the neuroin pathogenesis of PD and may offer new treatment strategies nflammatory to slow down the progression of Parkinso on's disease. .
| Sarkar, Souvarish; Malovic, Emir; Sarda, Deeksha et al. (2018) Characterization and comparative analysis of a new mouse microglial cell model for studying neuroinflammatory mechanisms during neurotoxic insults. Neurotoxicology 67:129-140 |
| Gordon, Richard; Albornoz, Eduardo A; Christie, Daniel C et al. (2018) Inflammasome inhibition prevents ?-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10: |
