PubMed_ArguminSci  

PubMed:29038245 JSONTXT 6 Projects

Annnotations TAB TSV DIC JSON TextAE Lectin_function IAV-Glycan

Id Subject Object Predicate Lexical cue
T1 118-336 DRI_Outcome denotes Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD.
T2 337-458 DRI_Challenge denotes Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear.
T3 459-643 DRI_Background denotes Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening.
T4 644-870 DRI_Background denotes As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations.
T5 871-980 DRI_Outcome denotes In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake.
T6 981-1230 DRI_Outcome denotes We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX.
T7 1231-1429 DRI_Background denotes Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes.
T8 1430-1533 DRI_Background denotes Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway.
T9 1534-1621 DRI_Background denotes Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening.
T10 1622-1902 DRI_Background denotes Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective.
T11 1903-2035 DRI_Challenge denotes These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant
T12 2068-2193 DRI_Challenge denotes STATEMENT Cognitive dysfunction and dementia are common features of Parkinson's disease (PD), causing significant disability.
T13 2194-2265 DRI_Background denotes Mutations in LRRK2 represent the most common known genetic cause of PD.
T14 2266-2279 DRI_Outcome denotes We found that
T15 2296-2497 DRI_Outcome denotes mutations increased dendritic and mitochondrial calcium uptake in cortical neurons and familial PD patient fibroblasts, accompanied by increased expression of the mitochondrial calcium transporter MCU.
T16 2498-2666 DRI_Background denotes Blocking the ERK1/2-dependent upregulation of MCU conferred protection against mutant LRRK2-elicited dendrite shortening, as did inhibiting MCU-mediated calcium import.
T17 2667-2756 DRI_Background denotes Conversely, stimulating the export of calcium from mitochondria was also neuroprotective.
T18 2757-2971 DRI_Challenge denotes These results implicate increased susceptibility to mitochondrial calcium overload in LRRK2-driven neurodegeneration, and suggest possible interventions that may slow the progression of cognitive dysfunction in PD.