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| Open AccessNetwork connectivity determines cortical thinning in early Parkinson’s disease progression
In Parkinson’s disease (PD), neurodegeneration spreads from the brainstem to the cerebral cortex. Here, in a longitudinal study of PD patients, the authors found that cortical thinning followed neural connectivity from a “disease reservoir”.
- Y. Yau
- , Y. Zeighami
- & A. Dagher
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| Open AccessPINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress
Mutations in the mitochondrial kinase PINK1 result in familial Parkinson’s disease. Here the authors show that LETM1, a mitochondrial inner membrane protein, is a substrate of PINK1 that regulates Ca2+ handling in mitochondria in response to mitochondrial toxins.
- En Huang
- , Dianbo Qu
- & David S. Park
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| Open AccessLoss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c
Mutations inCHCHD2 are associated with Parkinson’s disease. Here the authors investigate the physiological and pathological roles of CHCHD2 in Drosophilaand mammalian cells, and find that it regulates mitochondrial respiration through stabilizing cytochrome c.
- Hongrui Meng
- , Chikara Yamashita
- & Nobutaka Hattori
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| Open AccessDefective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Accumulated damage to mitochondrial DNA (mtDNA) occurs during the ageing process and neurodegenerative disease. Here, the authors show that mtDNA copy number increases in an age-dependent manner in substantia nigra of healthy individuals, but not in individuals with Parkinson disease.
- Christian Dölle
- , Irene Flønes
- & Charalampos Tzoulis
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| Open AccessStructural basis of synaptic vesicle assembly promoted by α-synuclein
α-synuclein, a protein associated to Parkinson's disease, is involved in synaptic vesicle interaction and assembly. Here, the authors use NMR spectroscopy and super-resolution microscopy to unveil the nature and molecular mechanism of α-synuclein-mediated synaptic vesicle clustering.
- Giuliana Fusco
- , Tillmann Pape
- & Alfonso De Simone
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| Open AccessThe Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway
Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson’s disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.
- Carla F. Bento
- , Avraham Ashkenazi
- & David C. Rubinsztein
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| Open AccessUbiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1
Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.
- Frederick C. Nucifora Jr
- , Leslie G. Nucifora
- & Christopher A. Ross
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| Open AccessMutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism–dystonia
Karin Tuschl, Philippa Mills and colleagues report mutations in the manganese (Mn) transporter gene SLC39A14in childhood-onset parkinsonism-dystonia. Using functional recapitulation, the authors also show that slc39A14 loss-of-function in zebrafish can lead to Mn dysregulation and locomotor impairment.
- Karin Tuschl
- , Esther Meyer
- & Stephen W. Wilson
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| Open AccessIntracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites
α-synuclein is a protein linked to the occurrence of Parkinson's disease. Here, the authors use time-resolved in-cell NMR spectroscopy to study the repair of methionine-oxidized α-synuclein by endogenous cellular enzymes.
- Andres Binolfi
- , Antonio Limatola
- & Philipp Selenko
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| Open AccessImpairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease
PLA2g6 regulates store-operated Ca2+ entry and is linked to Parkinson’s disease. Here, Zhou et al find faulty PLA2g6-dependent Ca2+signaling in idiopathic PD patients, and show that its impairment triggers autophagic dysfunction and loss of dopaminergic neurons in a new PLA2g6 ex2KO mouse model.
- Qingde Zhou
- , Allen Yen
- & Victoria M. Bolotina
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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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The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome
Mutations in the gene encoding DJ-1 are associated with early-onset familial forms of Parkinson’s disease, and several different molecular functions have been attributed to this protein. Moscovitz et al.show that DJ-1 physically binds the 20S proteasome and inhibits its degradation activity.
- Oren Moscovitz
- , Gili Ben-Nissan
- & Michal Sharon
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Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation
Small molecules that inhibit α-synuclein misfolding may have potential in the treatment of Parkinson’s disease. Fonseca-Ornelas et al.show that several of these molecules fail to block misfolding in the presence of membrane vesicles, and reveal how phtalocyanine tetrasulfonate, in contrast, overcomes this effect.
- Luis Fonseca-Ornelas
- , Sybille E. Eisbach
- & Markus Zweckstetter
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| Open AccessActivated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF
In the adult brain, the neurotrophic factor basic fibroblast growth factor (bFGF) is predominantly secreted by astrocytes. Here the authors use optogenetics to activate astrocytes, leading to release of bFGF, inducing enhanced dopaminergic differentiation of neural progenitors and promoting brain repair in a mouse Parkinson’s disease model.
- Fan Yang
- , Yunhui Liu
- & Liping Wang
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Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7
The kinase LRRK2 is implicated in Parkinson’s disease progression and is known to be phosphorylated. Chia et al.show that this phosphorylation is mediated by the kinase CK1a, and is required for the recruitment of LRRK2 to Golgi-derived vesicles, suggesting a role for this protein in Golgi maintenance.
- Ruth Chia
- , Sara Haddock
- & Mark R. Cookson
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Article
| Open AccessDrp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo
Mitochondrial dysfunction has been associated with Parkinson’s disease but effective therapies targeting this pathway are yet to be developed. Here the authors show that inhibition of the mitochondrial fission protein Drp-1 using genetic or small-molecule approaches in mouse models of the disease, leads to improvements in the pathology.
- Phillip M. Rappold
- , Mei Cui
- & Kim Tieu
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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia
Parkinson’s disease and L-DOPA-induced dyskinesia are both associated with imbalances in activity between populations of spiny projection neurons. Fieblinger et al.show that homeostatic adaptations in excitability are engaged by these disease states, but synaptic strengths are not scaled accordingly.
- Tim Fieblinger
- , Steven M. Graves
- & D. James Surmeier
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A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease
Mitochondrial dysfunction is associated with a number of neurodegenerative diseases. Szelechowski et al.take advantage of a viral protein that suppresses apoptosis in neurons to isolate a peptide that protects mitochondria and reduces neuronal cell death in a mouse model of Parkinson’s disease.
- Marion Szelechowski
- , Alexandre Bétourné
- & Daniel Gonzalez-Dunia
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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
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| Open AccessParkin regulates kainate receptors by interacting with the GluK2 subunit
Loss-of-function mutations in the PARK2gene are implicated in autosomal recessive juvenile parkinsonism, but the mechanisms are unclear. Here, the authors show that these mutations cause accumulation of the kainate receptor subunit GluK2 in the plasma membrane of neurons, which facilitates neuronal death.
- AnnaMaria Maraschi
- , Andrea Ciammola
- & Jenny Sassone
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Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein
Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al. report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.
- Eun-Jin Bae
- , Na-Young Yang
- & Seung-Jae Lee
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| Open AccessModest CaV1.342-selective inhibition by compound 8 is β-subunit dependent
Compound 8-1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6(1H,3H,5H)-trione was previously reported to be a selective inhibitor of the CaV1.3 calcium channel. Now, Huang et al. demonstrate that selectivity towards CaV1.3 relative to CaV1.2 is dependent on the type of β-subunit and CaV1.3 splice variant assayed.
- Hua Huang
- , Cheng Yang Ng
- & Tuck Wah Soong
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iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
- David C. Schöndorf
- , Massimo Aureli
- & Michela Deleidi
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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour
α-synuclein is a protein whose aberrant aggregation is associated with Parkinson’s disease. Here, Fusco et al.characterize α-synuclein bound to lipid membranes using a combination of solution and solid-state NMR spectroscopy and provide insights into the molecular processes associated with the aggregation of this protein.
- Giuliana Fusco
- , Alfonso De Simone
- & Gianluigi Veglia
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| Open AccessMutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy
Parkinson’s disease can be caused by a rare mutation in the protein VPS35, but the mechanism responsible for this is largely unknown. Here, Zavodszky et al.show that this mutation leads to defects in the recruitment of endosomal protein sorting machinery and consequent inhibition of autophagy in cells.
- Eszter Zavodszky
- , Matthew N.J. Seaman
- & David C. Rubinsztein
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| Open AccessRhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels
Glutathione is a key antioxidant that plays an important neuroprotective role in the brain. Here, Kinoshita et al.show that levels of glutathione exhibit diurnal fluctuations that are indirectly regulated by the microRNA miR-96-5p, and that this microRNA plays a neuroprotective role against oxidative stress.
- Chisato Kinoshita
- , Koji Aoyama
- & Toshio Nakaki
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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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| Open AccessA molecular explanation for the recessive nature of parkin-linked Parkinson’s disease
Mutations in the E3 ubiquitin ligase parkin are associated with juvenile Parkinson’s disease. Here the authors report the solution structure of the Parkin RING2 domain, revealing how disease-associated mutations affect its function and providing a molecular explanation for the recessive nature of the disease.
- Donald E. Spratt
- , R Julio Martinez-Torres
- & Gary S. Shaw
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| Open AccessStructure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
The Parkinson’s disease-associated protein Parkin regulates the fate of damaged mitochondria by ubiquitinating mitochondrial substrates. Riley et al. present the crystal structure of the Parkin-R0RBR domain, providing new insight into the catalytic mechanism of the enzyme.
- B.E. Riley
- , J.C. Lougheed
- & J.A. Johnston
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Sulfhydration mediates neuroprotective actions of parkin
The gasotransmitter hydrogen sulfide signals by sulfide modification of target proteins. Vandiver and colleagues study the sulfhydration of parkin by hydrogen sulfide and find that sulfhydration stimulates its activity, and that this activity is reduced in patients with Parkinson’s disease.
- M. Scott Vandiver
- , Bindu D. Paul
- & Solomon H. Snyder
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Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia
Parkinson’s disease is associated with the accumulation of abnormal aggregates of α-synuclein and microglial neuroinflammation. Kim et al. show that α-synuclein oliogomers released by neurons activate microglia by stimulating Toll-like receptor 2 signalling in these cells.
- Changyoun Kim
- , Dong-Hwan Ho
- & Seung-Jae Lee
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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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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology
The protein α-synuclein is implicated in Parkinson's disease. Rhinn and colleagues perform gene expression analysis and find that specific α-synuclein transcripts are preferentially associated with Parkinson's disease, and that they potentiate the accumulation of α-synuclein protein.
- Herve Rhinn
- , Liang Qiang
- & Asa Abeliovich
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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