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Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al.show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.
- Kunihiko Kanatsu
- , Yuichi Morohashi
- & Takeshi Iwatsubo
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NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization
Nuclear transcription factor-Y is a cell cycle regulator that remains active in differentiated neurons. Here, Yamanaka et al.show that nuclear transcription factor-Y activity in neurons is required for the proper organization of the endoplasmic reticulum.
- Tomoyuki Yamanaka
- , Asako Tosaki
- & Nobuyuki Nukina
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A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson’s disease models
Monoamine oxidase B is an enzyme that is unusually active in Parkinson’s disease, a feature that makes it an ideal diagnostic biomarker. Here, Li et al. create a highly specific fluorogenic probe that can selectively detect monoamine oxidase B activity in vivoto effectively diagnose Parkinson’s disease.
- Lin Li
- , Cheng-Wu Zhang
- & Shao Q. Yao
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Article
| Open AccessRETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Pericytes are cells in the blood–brain barrier that degenerate with the onset of Alzheimer's disease. Here, Sagare et al. show that pericyte loss contributes to disease onset by promoting amyloid-beta accumulation, tau pathology and early loss of neuronal cells.
- Abhay P. Sagare
- , Robert D. Bell
- & Berislav V. Zlokovic
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Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
The enzyme NEU1 negatively regulates lysosomal exocytosis in various cell types. Annunziata et al.show that mice deficient in NEU1 display Alzheimer’s disease-like pathology and that direct brain administration of NEU1 reduces pathology in an Alzheimer’s disease mouse model.
- Ida Annunziata
- , Annette Patterson
- & Alessandra d’Azzo
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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
Misfolding and aggregation of TAR DNA-binding protein 43 is implicated in various neurodegenerative diseases. Chang et al. show that aggregation of this protein is regulated by heat-shock proteins, which act to reduce the amount of pathological protein aggregates.
- Hsiang-Yu Chang
- , Shin-Chen Hou
- & I-Fan Wang
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Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration
Heat shock factor-1 is a transcriptional regulator of heat shock proteins that is implicated in neurodegeneration. Kondo and colleagues study the effects of deleting heat shock factor-1 in a mouse model of muscular dystrophy and find that this augments the condition via the accumulation of androgen receptors.
- Naohide Kondo
- , Masahisa Katsuno
- & Gen Sobue
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CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease
L-type calcium channels comprising the CaV1.3 subunit have been linked to the generation of mitochondrial oxidant stress in Parkinson’s disease. Kang et al. identify pyrimidine-2,4,6-triones as a potential molecular scaffold, which they modify to develop a potent and highly selective CaV1.3 antagonist.
- Soosung Kang
- , Garry Cooper
- & Richard B. Silverman
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Article
| Open AccessPrion protein facilitates uptake of zinc into neuronal cells
Prion proteins are implicated in a range of neurodegenerative diseases, which are, in part, due to a disruption of metal homeostasis. Wattet al.use selective antagonists to show that prion proteins mediate zinc uptake by interacting with GluA2-lacking, GluA1-containing AMPA receptors.
- Nicole T. Watt
- , David R. Taylor
- & Nigel M. Hooper
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Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo
The amyloid beta peptide can aggregate into insoluble plaques, which may indicate the onset of Alzheimer's disease. In a mouse model of Alzheimer's disease, Cao and colleagues report a phenotype of altered connectivity in the olfactory neuronal circuit that precedes amyloid plaque deposition.
- Luxiang Cao
- , Benjamin R. Schrank
- & Mark W. Albers
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| Open AccessPINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria
The kinase PINK1 is mutated in Parkinson's disease and accumulates in defective mitochondria, where it recruits Parkin. Here, PINK1 is shown to be autophosphorylated and this is required for the localization of PINK1 to mitochondria with a reduced membrane potential, and for the recruitment of Parkin.
- Kei Okatsu
- , Toshihiko Oka
- & Noriyuki Matsuda
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Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells
Mutations in parkin, an ubiquitin ligase, cause an inherited form of Parkinson's disease. Here, Jianget al. generate induced pluripotent stem cells from two patients with parkin mutations and find that neurons derived from the stem cells have defects in dopamine release, dopamine uptake and oxidative metabolism.
- Houbo Jiang
- , Yong Ren
- & Jian Feng
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| Open AccessParkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus
Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.
- Michael J. Devine
- , Mina Ryten
- & Tilo Kunath
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TorsinA participates in endoplasmic reticulum-associated degradation
The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.
- Flávia C. Nery
- , Ioanna A. Armata
- & Xandra O. Breakefield
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| Open AccessInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.
- Darragh B. Freir
- , Andrew J. Nicoll
- & John Collinge
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Article
| Open AccessRapid cell-surface prion protein conversion revealed using a novel cell system
The study of prion diseases has been hampered as there is no method to distinguish newly formed abnormal prion protein conformers. Here, the authors describe a method to study newly formed abnormal prion protein and demonstrate that it is produced within 1 minute of cell exposure to prions.
- R. Goold
- , S. Rabbanian
- & S.J. Tabrizi
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The acetylation of tau inhibits its function and promotes pathological tau aggregation
Phosphorylation of the microtubule-associated protein tau is associated with disease, but other post-translational modifications of tau are not well studied. Here, Cohenet al. study the acetylation of tau and suggest that this form of the protein may be associated with tauopathies.
- Todd J. Cohen
- , Jing L. Guo
- & Virginia M. Y. Lee