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| Open AccessParkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation
ß-Sheet-rich aggregates of α-synuclein (αS) characterize Parkinson's disease (PD) and recent work suggests that αS exists as α-helix-rich tetramers and related low-nmultimers in normal cells. Here the authors show that αS mutations associated with familial PD decrease the intraneuronal tetramer:monomer ratio and are correlated with neurotoxicity.
- Ulf Dettmer
- , Andrew J. Newman
- & Dennis Selkoe
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| Open AccessGenome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
- Naomi Kouri
- , Owen A. Ross
- & Dennis W. Dickson
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| Open AccessBruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury
Activation of inflammasome contributes to several pathologies. Here, the authors show that Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation, and that blocking it with the FDA-approved inhibitor ibrutinib limits tissue damage in a mouse model of ischaemic stroke.
- Minako Ito
- , Takashi Shichita
- & Rimpei Morita
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Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons
Abnormal accumulation of TDP-43 and FUS proteins is found in a neurodegenerative disease amyotrophic lateral sclerosis. Here the authors show by modelling the disease in worms that these proteins activate local and distal immune responses, and blocking this pathway in neurons ameliorates the disease.
- Julie Vérièpe
- , Lucresse Fossouo
- & J Alex Parker
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Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
Tuberous sclerosis complex (TSC) arises from mutations in an activator of the small GTPase Rheb. Here the authors show that syntenin binds to GDP-bound Rheb, and loss of this interaction in TSC leads to increased syntenin expression and downstream signalling defects leading to aberrant spine synapse morphogenesis.
- Hiroko Sugiura
- , Shin Yasuda
- & Kanato Yamagata
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| Open AccessOligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice
Whether oligodendrocytes have a role in the development of chronic pain is not clear. Here the authors show that oligodendrocyte depletion causes a neuropathic pain that sets in before demyelination and is independent of immune cell activation and infiltration.
- Simon Gritsch
- , Jianning Lu
- & Rohini Kuner
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| Open AccessDeficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice
Synapse degeneration is an early feature of neurodegenerative diseases. Here the authors show that Wnts are endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.
- Soledad Galli
- , Douglas M. Lopes
- & Patricia C. Salinas
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| Open AccessIncreasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations
Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophilalocomotor behaviour that can be reversed by enhancing tubulin acetylation.
- Vinay K. Godena
- , Nicholas Brookes-Hocking
- & Kurt J. De Vos