Suchergebnisse

Exposure to pesticides such as rotenone is a risk factor for Parkinson's disease. Dopaminergic neurons are especially sensitive to the toxicity of compounds that inhibit the mitochondrial respiratory chain such as rotenone and 1-methyl-4-phenylpyridinium (MPP+). However, there is scarce information on their effects on glia. To evaluate whether these neurotoxicants affect the immune response of glia, primary mouse mixed glial and microglial cultures were treated with interleukin (IL) 4 in the absence and presence of MPP+ or rotenone. Using qRTPCR or western blot, we determined the expression of anti-inflammatory markers, the CD200R1 microglial receptor and its ligand CD200, and genes regulating glycolysis and oxidative metabolism. ATP and lactate levels were additionally determined as an index of cell metabolism. Microglial phagocytosis was also evaluated. MPP+ and rotenone clearly abrogated the IL4-induced expression of anti-inflammatory markers in mixed glial cultures. CD200 and CD200R1 expression and microglia phagocytosis were also affected by the neurotoxicants. Changes in the mRNA expression of the molecules regulating glycolysis and oxidative metabolism, as well as in ATP levels and lactate release suggested that metabolic reprogramming in response to MPP+ and rotenone differs between microglial and mixed glial cultures. These findings support the hypothesis that parkinsonian neurotoxicants may impair brain immune response altering glial cell metabolism. ; This study was supported by grant PI15/00033 from the Instituto de Salud Carlos III (Spain) with joint financing by FEDER funds from the European Union. NR-L was recipient of a predoctoral FPU contract from the Spanish Ministerio de Ciencia, Innovación y Universidades (FPU13/05491). ; Peer reviewed

A deeper understanding of early disease mechanisms occurring in Parkinson's disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients' networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases. ; Research from the authors' laboratories is supported by the European Research Council-ERC (2012-StG-311736-PD-HUMMODEL), the MESOBRAIN project from the European Union's Horizon 2020 research and innovation (grant agreement No. 713140), the Spanish Ministry of Economy and Competitiveness-MINECO (RTI2018-095377-B-100, FIS2016-78507-C2-2-P, PID2019-108842GB-C21) the Spanish Ministry of Economy and Competitiveness-MINECO/AEI/FEDER, UE (BFU2016-80870-P) and the Spanish Ministry of Economy and Competitiveness- AEI/10.13039/501100011033 (PID2019-108792GB-I00), Instituto de Salud Carlos III-ISCIII/FEDER (Red de Terapia Celular - TerCel RD16/0011/0024 and RD16/0011/0025), AGAUR (2017-SGR-899 and 2017-SGR-1061), and CERCA Program/Generalitat de Catalunya. M.P.E. was partially supported by a Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR) of the Government of Catalonia (2017 BP 00133). L.B. is the recipient of a pre-doctoral fellowship FPI (BES-2017-080579) from the Spanish Ministry of Economy and Competitiveness (MINECO). G.C. was partially supported by pre-doctoral fellowship from Spanish Economy and Competitiveness-MINECO (BES-2014-069603).