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| Open AccessFunctional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease
Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.
- Nicolai Franzmeier
- , Julia Neitzel
- & Balebail Ashok Raj
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Article
| Open AccessPosterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect
Projections from the anterior and posterior basolateral amygdala (pBLA) to the ventral hippocampus CA1 (vCA1) are heterogenous. Here the authors show that activating the pathway from pBLA to vCA1 calbindin 1 positive neurons has an anxiolytic effect in approach-avoidance tasks in mice.
- Guilin Pi
- , Di Gao
- & Jian–Zhi Wang
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Article
| Open AccessClinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma
Detection of Alzheimer’s disease (AD) biomarkers from patients’ blood is challenging because these are present in very low concentrations in the plasma. Here the authors develop a sensor array of densely aligned single-walled carbon nanotubes for clinically accurate detection of femtomolar AD biomarkers in human plasma samples.
- Kayoung Kim
- , Min-Ji Kim
- & Chan Beum Park
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Article
| Open AccessStructural heterogeneity of α-synuclein fibrils amplified from patient brain extracts
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are characterized by the pathological accumulation of α-synuclein. Here the authors employ fluorescent probes, electron microscopy and NMR spectroscopy to study the properties of α-synuclein aggregates that were amplified from patient brain extracts and observe a greater structural diversity among PD patients compared to MSA patients.
- Timo Strohäker
- , Byung Chul Jung
- & Markus Zweckstetter
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Article
| Open AccessUnstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.
- Rahel T. Florian
- , Florian Kraft
- & Christel Depienne
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Article
| Open AccessCryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue
Alzheimer’s disease is characterised by the deposition of Aβ amyloid fibrils and tau protein neurofibrillary tangles. Here the authors use cryo-EM to structurally characterise brain derived Aβ amyloid fibrils and find that they are polymorphic and right-hand twisted, which differs from in vitro generated Aβ fibrils.
- Marius Kollmer
- , William Close
- & Marcus Fändrich
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Article
| Open AccessStructural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.
- Yu-Jie Li
- , Yu-Lu Cao
- & Song Gao
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Article
| Open AccessNon-coding variability at the APOE locus contributes to the Alzheimer’s risk
Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.
- Xiaopu Zhou
- , Yu Chen
- & Nancy Y. Ip
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| Open AccessInterpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline
Convolutional neural networks have been applied to various areas of medical imaging and histology. Here the authors develop an automated approach using interpretable neural networks to determine Alzheimer’s disease plaque and cerebral amyloid angiopathy burden in post-mortem human brain tissue.
- Ziqi Tang
- , Kangway V. Chuang
- & Brittany N. Dugger
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Article
| Open AccessA molecular mechanism for transthyretin amyloidogenesis
A number of disease-causing human transthyretin (TTR) mutations are known to lead to amyloid formation. Here the authors combine neutron crystallography, native mass spectrometry and modelling studies to characterize the T119M and S52P-TTR mutants, providing mechanistic insights into TTR amyloidosis.
- Ai Woon Yee
- , Matteo Aldeghi
- & V. Trevor Forsyth
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Article
| Open AccessSingle-cell RNA sequencing reveals midbrain dopamine neuron diversity emerging during mouse brain development
Midbrain dopamine (mDA) neurons are significantly associated with Parkinson’s disease and yet there is no systematic molecular classification of these heterogenous group of cells. Here authors use single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3 (broad mDA neuronal marker) to identify and characterize seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons.
- Katarína Tiklová
- , Åsa K. Björklund
- & Thomas Perlmann
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| Open AccessUncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference
Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.
- Alexandra L Young
- , Razvan V Marinescu
- & Ansgar J Furst
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Article
| Open AccessEpigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by aggregation of Tau, encoded by MAPT. Here, the authors perform an EWAS for PSP in prefrontal lobe tissue and find hypermethylation of DLX1 and its antisense transcript DLX1AS to associate with MAPT expression.
- Axel Weber
- , Sigrid C. Schwarz
- & Ulrich Müller
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| Open AccessDirect reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a
Fibroblasts can be reprogrammed into induced neural stem cells (iNSCs) using transcription factors expressed in neural progenitors. Here the authors show that Ptf1a, which is normally expressed in postmitotic neurons, can reprogram fibroblasts to iNSCs through Notch independent interaction with Rbpj.
- Dongchang Xiao
- , Xiaoning Liu
- & Mengqing Xiang
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Article
| Open AccessC9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation
Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors show that (GGGGCC) n translation can initiate without a 5′-cap, and this cap-independent translation is upregulated by stress mediated through eIF2α phosphorylation.
- Weiwei Cheng
- , Shaopeng Wang
- & Shuying Sun
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Article
| Open AccessLoss of mtDNA activates astrocytes and leads to spongiotic encephalopathy
Astrocytes in the brain are metabolically dynamic. Here, Ignatenko, Chilov and colleagues delete mitochondrial DNA (mtDNA) in a cell type specific manner, and show that inactivation of mtDNA helicase Twinkle in astrocytes leads to spongiotic encephalopathy.
- Olesia Ignatenko
- , Dmitri Chilov
- & Anu Suomalainen
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Article
| Open AccessEvidence for causal top-down frontal contributions to predictive processes in speech perception
The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.
- Thomas E. Cope
- , E. Sohoglu
- & James B. Rowe
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Article
| Open AccessRods progressively escape saturation to drive visual responses in daylight conditions
Rod photoreceptors are thought to be saturated under bright light. Here, the authors describe the physiological parameters that mediate response saturation of rod photoreceptors in mouse retina, and show that rods can drive visual responses in photopic conditions.
- Alexandra Tikidji-Hamburyan
- , Katja Reinhard
- & Thomas A. Münch
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Article
| Open AccessHIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration
HIV infection results in elevated beta-amyloid (Aβ) levels in the brain, but the underlying mechanisms are unclear. Here, the authors show that amyloid precursor protein inhibits virion production and that HIV Gag, counteracting this antiviral function, results in secretase-dependent Aβ production and neuron degeneration.
- Qingqing Chai
- , Vladimir Jovasevic
- & Mojgan H. Naghavi
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| Open AccessNovel genetic loci associated with hippocampal volume
The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.
- Derrek P. Hibar
- , Hieab H. H. Adams
- & M. Arfan Ikram
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Article
| Open AccessBasal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology
Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.
- Taylor W. Schmitz
- , R. Nathan Spreng
- & Ansgar J. Furst
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Article
| Open AccessMonitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging
Sensitive and label-free imaging methods to visualize nerve degeneration are currently lacking. Here authors show that stimulated Raman scattering (SRS) microscopy can be used to monitor peripheral nerve degeneration in mouse models of amyotrophic lateral sclerosis (ALS) and in postmortem tissue from ALS patients.
- Feng Tian
- , Wenlong Yang
- & Kevin Eggan
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| Open AccessRapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway
The elucidation of amyloid nucleation mechanisms remains challenging as early oligomeric intermediates are transient and difficult to distinguish. Here the authors use Aβ- polyglutamine hybrid peptides designed to slow and limit amyloid maturation to provide insights into the structures of Aβ self-assembly intermediates.
- Pinaki Misra
- , Ravindra Kodali
- & Ronald Wetzel
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Article
| Open AccessRegulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes
The molecular mechanisms regulating myelination are only partially understood. Here authors show that Tsc1ablation in oligodendrocyte lineage activates ER stress and apoptotic programs in mice, and that enhancing PERK-eIF2α signalling partially rescues the myelination defects in Tsc1 mutants.
- Minqing Jiang
- , Lei Liu
- & Q. Richard Lu
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Article
| Open AccessCCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
Ian Blair and colleagues use genome-wide linkage analysis and whole exome sequencing to identify mutations in the CCNF gene in large cohorts of amyotrophic lateral sclerosis and frontotemporal dementia patients. In addition to validating the mutations in international cohorts, the authors also show that mutant CCNFgene product affects ubiquitination and protein degradation in cultured cells.
- Kelly L. Williams
- , Simon Topp
- & Ian P. Blair
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Article
| Open AccessPromotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults
Mitochondrial dysfunction occurs in Parkinson's disease, although the underlying mechanisms are unclear. Here, the authors find necdin works to stabilise the mitochondrial regulator PGC-1α, and that overexpression of necdin protects against MPTP-mediated neurodegeneration both in vitro and in vivo.
- Koichi Hasegawa
- , Toru Yasuda
- & Kazuaki Yoshikawa
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Article
| Open AccessALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function
The mechanism by which FUS mutations cause familial ALS remains unclear. Here, the authors use mouse transgenic models to show that a toxic gain-of-function underlies motor neuron degeneration, and that the toxicity of mutant FUS does not depend on a loss or excess of FUS activity.
- Aarti Sharma
- , Alexander K. Lyashchenko
- & Neil A. Shneider
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| Open AccessNitric oxide mediates glial-induced neurodegeneration in Alexander disease
Alexander disease is a rare neurological disorder caused by mutations in GFAP, yet it is unclear how glial disruptions lead to neural death. Here, Wang et al. identify a mechanism by which glial-derived nitric oxide leads to neuronal degeneration in fly and mouse models of the disease.
- Liqun Wang
- , Tracy L. Hagemann
- & Mel B. Feany
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| Open AccessBreaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Immunosuppression has been unsuccessful in treatment of Alzheimer’s disease. Here the authors show in a mouse model of the disease that transient inhibition of regulatory T cells mitigates amyloid plaque pathology and reverses cognitive decline, whereas augmenting these cells worsens the pathology.
- Kuti Baruch
- , Neta Rosenzweig
- & Michal Schwartz
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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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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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| Open AccessFoxp1-mediated programming of limb-innervating motor neurons from mouse and human embryonic stem cells
The differentiation of spinal motor neurons (MNs) from mouse and human embryonic stem cells provides opportunities to model MN development and disease, but most protocols produce only a subset of the MN subtypes found in vivo. Here the authors show that limb projecting lateral motor column MNs can be efficiently generated though the expression of Foxp1.
- Katrina L. Adams
- , David L. Rousso
- & Bennett G. Novitch
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Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols
The protein frataxin has a role in iron–sulfur clusters biosynthesis that is still elusive. Here, the authors present a novel alkylation assay for the detection of persulfide, an intermediate in this process, and describe the function of frataxin in the control of persulfide transfer.
- Aubérie Parent
- , Xavier Elduque
- & Benoit D’Autréaux
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Evidence for zoonotic potential of ovine scrapie prions
Scrapie, a form of prion disease that affects sheep and goats, is believed not to be transmissible to humans. Using transgenic mice expressing human prion protein as a model of cross-species prion transmission, the authors show that ovine scrapie may possess potential to be passed on to humans.
- Hervé Cassard
- , Juan-Maria Torres
- & Olivier Andréoletti
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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
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Article
| Open AccessPICALM modulates autophagy activity and tau accumulation
The protein PICALM/CALM is implicated in Alzheimer’s disease (AD) pathology, but it is unclear how. In this study, the authors show that CALM regulates clearance of the protein tau, which is also implicated in AD pathology, by facilitating endocytosis-dependent autophagy.
- Kevin Moreau
- , Angeleen Fleming
- & David C. Rubinsztein
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Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients
TDP-43 proteinopathies are characterized by TDP-43 aggregates but the relationship of these aggregates to the pathogenesis is still not well defined. Here, the authors show that the recombinant full-length human TDP-43 forms oligomers that are neurotoxic, can promote the formation of A-beta amyloid oligomers in vitroand can be detected in postmortem brain of patients.
- Yu-Sheng Fang
- , Kuen-Jer Tsai
- & Yun-Ru Chen
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Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype
The yeast prion Sup35/[PSI+] confers a translation termination defect in its amyloid form. Pezza et al.reveal that aggregated Sup35 retains translation termination activity, and find that fluctuations in the size and composition of aggregates play an important role in determining their activity and toxicity.
- John A. Pezza
- , Janice Villali
- & Tricia R. Serio
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| Open AccessPrion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked
Prions (PrP) are infectious agents that cause lethal neurodegenerative diseases. Here the authors study the kinetics of prion propagation in mice and show that the onset of neuropathology occurs during the late phase of disease and is hypothesized to be due to increases in a toxic isoform of PrP that is different from the infectious species.
- Malin K. Sandberg
- , Huda Al-Doujaily
- & John Collinge
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Article
| Open AccessEXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.
- Veronika Boczonadi
- , Juliane S. Müller
- & Rita Horvath
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Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model
Altered GABAergic synaptic transmission is implicated in Alzheimer’s disease pathology. Here, Wu et al. show that GABA content is increased in brain samples from human patients and that in mouse models of the disease, the increase in GABA leads to an increase in tonic inhibition in the dentate gyrus.
- Zheng Wu
- , Ziyuan Guo
- & Gong Chen
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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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The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor
γ-secretase is a major target for treating Alzheimer’s disease (AD). Here, the authors screen various binding proteins against the γ-secretase complex and find that the evolutionarily conserved secretory protein ILEI interferes with γ-secretase-dependent production of β-amyloid, which is implicated in AD.
- Hiroshi Hasegawa
- , Lei Liu
- & Masaki Nishimura
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| Open AccessER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
Mutations in the protein TDP-43 are implicated in amyotrophic lateral sclerosis. Here, the authors show that mutant TDP-43 perturbs endoplasmic reticulum (ER)–mitochondria associations by altering interactions between the mitochondrial protein PTPIP51 and the ER protein VAPB.
- Radu Stoica
- , Kurt J. De Vos
- & Christopher C. J. Miller
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| Open AccessPathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb
Aggregation-prone forms of α-synuclein lead to degeneration of midbrain dopaminergic neurons, as seen in Parkinson’s disease, but less is known about the effects that the noxious protein has in other brain regions. Here, the authors investigate the effect of a pathological form of α-synuclein on the functional integration of new neurons into the olfactory bulb of adult mice.
- Johanna Neuner
- , Saak V. Ovsepian
- & Jochen Herms
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| Open AccessConformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum
Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.
- Giovanni Meli
- , Agnese Lecci
- & Antonino Cattaneo
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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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Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity
Cellular oxidative stress is implicated in neurodegeneration. Here, Kang et al.show that the receptor tyrosine kinase Flt3 and the signalling molecule PI3Kα play key roles in glutamate-mediated oxidative stress in neuronal cells, which can be prevented by Flt3- or PI3Kα-specific inhibitors.
- Yunyi Kang
- , Stefano Tiziani
- & Giovanni Paternostro