53 research outputs found
Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations
âLeucine-rich repeat kinase 2 (âLRRK2) mutations are the most common genetic cause of Parkinsonâs disease. âLRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinsonâs disease, but whether âLRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that âLRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase âαTAT1 prevents association of mutant âLRRK2 with microtubules, and the deacetylase inhibitor âtrichostatin A (âTSA) restores axonal transport. In vivo knockdown of the deacetylases âHDAC6 and âSirt2, or administration of âTSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinsonâs disease
Detection of symmetry in tachistoscopically presented dot patterns: Effects of multiple axes and skewing
Causal conditional reasoning and semantic memory retrieval: A test of the semantic memory framework
Event related message processing: perceiving and remembering changes in films with and without soundtrack
Enhancing television advertising: same-language subtitles can improve brand recall, verbal memory, and behavioral intent
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