Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex.
Abstract Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studi...
Source: Neurobiology of Disease - October 9, 2019 Category: Neurology Authors: Zhang B, Guo D, Han L, Rensing N, Satoh A, Wong M Tags: Neurobiol Dis Source Type: research

The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo.
let E Abstract The G2019S substitution in the kinase domain of LRRK2 (LRRK2G2019S) is the most prevalent mutation associated with Parkinson's disease (PD). Neurotoxic effects of LRRK2G2019S are thought to result from an increase in its kinase activity as compared to wild type LRRK2. However, it is unclear whether the kinase domain of LRRK2G2019S is sufficient to trigger degeneration or if the full length protein is required. To address this question, we generated constructs corresponding to the C-terminal domain of LRRK2 (ΔLRRK2). A kinase activity that was increased by G2019➔S substitution could be detect...
Source: Neurobiology of Disease - October 9, 2019 Category: Neurology Authors: Cresto N, Gaillard MC, Gardier C, Gubinelli F, Diguet E, Bellet D, Legroux L, Mitja J, Auregan G, Guillermier M, Josephine C, Jan C, Dufour N, Joliot A, Hantraye P, Bonvento G, Déglon N, Bemelmans AP, Cambon K, Liot G, Brouillet E Tags: Neurobiol Dis Source Type: research

Coding and non-coding transcriptome of mesial temporal lobe epilepsy: Critical role of small non-coding RNAs.
Abstract Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified ...
Source: Neurobiology of Disease - September 15, 2019 Category: Neurology Authors: Mills JD, van Vliet EA, Chen BJ, Janitz M, Anink JJ, Baayen JC, Idema S, Devore S, Friedman D, Diehl B, Thom M, Scott C, Thijs R, Aronica E, Devinsky O Tags: Neurobiol Dis Source Type: research

One-carbon metabolism supplementation improves outcome after stroke in aged male MTHFR-deficient mice.
This study reveals a critical role for one‑carbon supplementation, with 5-methylTHF, vitamin B12, and choline, in supporting improvement after ischemic stroke damage. PMID: 31525435 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - September 13, 2019 Category: Neurology Authors: Jadavji NM, Mosnier H, Kelly E, Lawrence K, Cruickshank S, Stacey S, McCall A, Dhatt S, Arning E, Bottiglieri T, Smith PD Tags: Neurobiol Dis Source Type: research

Pioglitazone improves working memory performance when administered in chronic TBI.
Abstract Traumatic brain injury (TBI) is a leading cause of long-term disability in the United States. Even in comparatively mild injuries, cognitive and behavioral symptoms can persist for years, and there are currently no established strategies for mitigating symptoms in chronic injury. A key feature of TBI-induced damage in acute and chronic injury is disruption of metabolic pathways. As neurotransmission, and therefore cognition, are highly dependent on the supply of energy, we hypothesized that modulating metabolic activity could help restore behavioral performance even when treatment was initiated weeks afte...
Source: Neurobiology of Disease - September 9, 2019 Category: Neurology Authors: McGuire JL, Correll EA, Lowery AC, Rhame K, Anwar FN, McCullumsmith RE, Ngwenya LB Tags: Neurobiol Dis Source Type: research

Sex-dependent impaired locomotion and motor coordination in the HdhQ200/200 mouse model of Huntington's Disease.
We report that female HdhQ200/200 mice display an earlier onset and more robust deterioration in spontaneous locomotion and motor coordination measured at 8 months of age compared to male HdhQ200/200 mice. Remarkably, HdhQ200/200 mice of both sexes exhibit comparable impaired spontaneous locomotion and motor coordination at 10 months of age and reach moribund stage by 12 months of age, demonstrating reduced life span in this model system. Histopathological analysis revealed enhanced mutant huntingtin protein aggregation in male HdhQ200/200 striatal tissue at 8 months of age compared to female HdhQ200/200. Functiona...
Source: Neurobiology of Disease - September 6, 2019 Category: Neurology Authors: Cao JK, Viray K, Zweifel L, Stella N Tags: Neurobiol Dis Source Type: research

Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with A β in a mice model of early-stage Alzheimer's disease.
Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with Aβ in a mice model of early-stage Alzheimer's disease. Neurobiol Dis. 2019 Sep 05;:104603 Authors: Caleb AA, Akiyama T, Kimura A, Kimura Y, Takahashi-Jitsuki A, Nakamura H, Makihara H, Masukawa D, Nakabayashi J, Hirano H, Nakamura F, Saito T, Saido T, Goshima Y Abstract Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by memory loss and neurotoxic amyloid beta (Aβ) plaques accumulation. Numerous pharmacological interventions targeting Aβ plaques accumulation hav...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Caleb AA, Akiyama T, Kimura A, Kimura Y, Takahashi-Jitsuki A, Nakamura H, Makihara H, Masukawa D, Nakabayashi J, Hirano H, Nakamura F, Saito T, Saido T, Goshima Y Tags: Neurobiol Dis Source Type: research

Friedreich ataxia- pathogenesis and implications for therapies.
Abstract Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur clust...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Delatycki MB, Bidichandani SI Tags: Neurobiol Dis Source Type: research

Diabetes mellitus in the young and the old: Effects on cognitive functioning across the life span.
Abstract Mild to moderate cognitive decrements are a well-known phenomenon associated with diabetes mellitus. In this review, we provide an overview of the cognitive consequences of type 1 and type 2 diabetes based on hallmark studies that follow patients over an extended period of time. In patients with type 1 diabetes, cognitive dysfunction appears soon after diagnosis and can be found in individuals of any age. The magnitude of these effects is generally modest, although their severity is especially pronounced in those with early onset type 1 diabetes (diagnosis before 7 years of age) or those who have develo...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: van Duinkerken E, Ryan CM Tags: Neurobiol Dis Source Type: research

Human NPCs can degrade α-syn fibrils and transfer them preferentially in a cell contact-dependent manner possibly through TNT-like structures.
Human NPCs can degrade α-syn fibrils and transfer them preferentially in a cell contact-dependent manner possibly through TNT-like structures. Neurobiol Dis. 2019 Sep 05;:104609 Authors: Grudina C, Kouroupi G, Nonaka T, Hasegawa M, Matsas R, Zurzolo C Abstract Parkinson's disease (PD) is the second most common neurodegenerative disorder whereby loss of midbrain dopaminergic neurons results in motor dysfunction. Transplantation of human induced pluripotent stem cells (iPSCs) into the brain of patients affected by PD is one of the therapeutic approaches that has gained interest to compensate for t...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Grudina C, Kouroupi G, Nonaka T, Hasegawa M, Matsas R, Zurzolo C Tags: Neurobiol Dis Source Type: research

A TrkB agonist and ampakine rescue synaptic plasticity and multiple forms of memory in a mouse model of intellectual disability.
Abstract Fragile X syndrome (FXS) is associated with deficits in various types of learning, including those that require the hippocampus. Relatedly, hippocampal long-term potentiation (LTP) is impaired in the Fmr1 knockout (KO) mouse model of FXS. Prior research found that infusion of brain-derived neurotrophic factor (BDNF) rescues LTP in the KOs. Here, we tested if, in Fmr1 KO mice, up-regulating BDNF production or treatment with an agonist for BDNF's TrkB receptor restores synaptic plasticity and improves learning. In hippocampal slices, bath infusion of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) completel...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Seese RR, Le AA, Wang K, Cox CD, Lynch G, Gall CM Tags: Neurobiol Dis Source Type: research

Subthalamic nucleus oscillations correlate with vulnerability to freezing of gait in patients with Parkinson's disease.
Abstract Freezing of gait (FOG) is a disabling clinical phenomenon often found in patients with advanced Parkinson's disease (PD). FOG impairs motor function, causes falls and leads to loss of independence. Whereas dual tasking that distracts patients' attention precipitates FOG, auditory or visual cues ameliorate this phenomenon. The pathophysiology of FOG remains unclear. Previous studies suggest that the basal ganglia are involved in the generation of FOG. Investigation of the modulation of neuronal activities within basal ganglia structures during walking is warranted. To this end, we recorded local field pote...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Chen CC, Yeh CH, Chan HL, Chang YJ, Tu PH, Yeh CH, Lu CS, Fischer P, Tinkhauser G, Tan H, Brown P Tags: Neurobiol Dis Source Type: research

The impact of silencing feed-forward parvalbumin-expressing inhibitory interneurons in the cortico-thalamocortical network on seizure generation and behaviour.
Abstract Feed-forward inhibition (FFI) is an essential mechanism within the brain to regulate neuronal firing and prevent runaway excitation. In the cortico-thalamocortical (CTC) network, fast spiking parvalbumin-expressing (PV+) inhibitory interneurons regulate the firing of pyramidal cells in the cortex and relay neurons in the thalamus. PV+ interneuron dysfunction has been implicated in several neurological disorders, including epilepsy. Previously, we demonstrated that loss of excitatory AMPA-receptors, specifically at synapses on PV+ interneuron in CTC feedforward microcircuits, occurs in the stargazer mouse ...
Source: Neurobiology of Disease - September 5, 2019 Category: Neurology Authors: Panthi S, Leitch B Tags: Neurobiol Dis Source Type: research

Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum.
Abstract Cerebellar Purkinje cell (PC) loss is a consistent pathological finding in autism. However, neural mechanisms of PC-dysfunction in autism remain poorly characterized. Glutamate receptor interacting proteins 1/2 (Grip1/2) regulate AMPA receptor (AMPAR) trafficking and synaptic strength. To evaluate role of PC-AMPAR signaling in autism, we produced PC-specific Grip1/2 knockout mice by crossing Grip2 conventional and Grip1 conditional KO with L7-Cre driver mice. PCs in the mutant mice showed normal morphology and number, and a lack of Grip1/2 expression. Rodent behavioral testing identified normal ambulation...
Source: Neurobiology of Disease - August 30, 2019 Category: Neurology Authors: Mejias R, Chiu SL, Han M, Rose R, Gil-Infante A, Zhao Y, Huganir RL, Wang T Tags: Neurobiol Dis Source Type: research

Corrigendum to "Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1G93A mouse model of ALS" Neurobiology of Disease 124 (2019) 340-352.
Corrigendum to "Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1G93A mouse model of ALS" Neurobiology of Disease 124 (2019) 340-352. Neurobiol Dis. 2019 Aug 27;:104558 Authors: Sengupta-Ghosh A, Dominguez SL, Xie L, Barck KH, Jiang Z, Earr T, Imperio J, Phu L, Budayeva HG, Kirkpatrick DS, Cai H, He D, Eastham-Anderson J, Ngu H, Foreman O, Hedehus M, Reichelt M, Hotzel I, Shang Y, Carano RAD, Ayalon G, Easton A PMID: 31471201 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - August 27, 2019 Category: Neurology Authors: Sengupta-Ghosh A, Dominguez SL, Xie L, Barck KH, Jiang Z, Earr T, Imperio J, Phu L, Budayeva HG, Kirkpatrick DS, Cai H, He D, Eastham-Anderson J, Ngu H, Foreman O, Hedehus M, Reichelt M, Hotzel I, Shang Y, Carano RAD, Ayalon G, Easton A Tags: Neurobiol Dis Source Type: research

Restored presynaptic synaptophysin and cholinergic inputs contribute to the protective effects of physical running on spatial memory in aged mice.
Abstract The effects of prolonged physical training on memory performance and underlying presynaptic mechanisms were investigated in old C57BL/6 mice. Training via voluntary running wheels was initiated at 16 months of age and continued for 5 months (1 h per day, 5 days per week), followed by testing of learning and memory functions and counting of presynaptic puncta and cholinergic inputs in the hippocampus. Trained old mice were compared to their age-matched sedentary controls and adult controls. This training strategy improved hippocampal-dependent spatial memory function tested via a novel location tas...
Source: Neurobiology of Disease - August 27, 2019 Category: Neurology Authors: Xu L, Long J, Su Z, Xu B, Lin M, Chen Y, Long D Tags: Neurobiol Dis Source Type: research

Multigenerational epigenetic inheritance: One step forward, two generations back.
Abstract Modifications to DNA and histone proteins serve a critical regulatory role in the developing and adult brain, and over a decade of research has established the importance of these "epigenetic" modifications in a wide variety of brain functions across the lifespan. Epigenetic patterns orchestrate gene expression programs that establish the phenotypic diversity of various cellular classes in the central nervous system, play a key role in experience-dependent gene regulation in the adult brain, and are commonly implicated in neurodevelopmental, psychiatric, and neurodegenerative disease states. In ...
Source: Neurobiology of Disease - August 27, 2019 Category: Neurology Authors: Tuscher JJ, Day JJ Tags: Neurobiol Dis Source Type: research

KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3 β pathway.
KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3β pathway. Neurobiol Dis. 2019 Aug 27;:104588 Authors: Wei T, Wang Y, Xu W, Yan L, Chen H, Yu Z Abstract Neuroinflammation may induce a phenotype switch to reactive astrogliosis in neurodegenerative disorders. The calcium-activated potassium channel (KCa3.1) is active in the phenotypic switch that occurs during astrogliosis in Alzheimer's disease and ischemic stroke. Here, transcriptome sequencing (RNA-Seq), immunohistochemistry, western blotting, pharmacological blockade, and cal...
Source: Neurobiology of Disease - August 27, 2019 Category: Neurology Authors: Wei T, Wang Y, Xu W, Yan L, Chen H, Yu Z Tags: Neurobiol Dis Source Type: research

TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration.
Abstract While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75NTR, a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75NTR. In addition, TrkB-agoAbs elicit muc...
Source: Neurobiology of Disease - August 27, 2019 Category: Neurology Authors: Guo W, Pang K, Chen Y, Wang S, Li H, Xu Y, Han F, Yao H, Liu H, Lopes-Rodrigues V, Sun D, Shao J, Shen J, Dou Y, You H, Wu W, Lu B Tags: Neurobiol Dis Source Type: research

Immunotherapy in Parkinson's disease: Current status and future directions.
Abstract Immunotherapeutic approaches for the treatment of Parkinson's disease (PD) and related synucleinopathies have steadily developed over the last two decades with several iterations currently being tested in clinical trials. Although classically characterized as a movement disorder, PD is also defined clinically by numerous non-motor features that can precede the motor manifestations and span across several decades of disease progression. Pathologically, PD is characterized by proteinaceous inclusions that largely consist of misfolded and aggregated forms of the protein, alpha-synuclein. Recent research has ...
Source: Neurobiology of Disease - August 24, 2019 Category: Neurology Authors: Chatterjee D, Kordower JH Tags: Neurobiol Dis Source Type: research

Obesity-related cognitive impairment: The role of endothelial dysfunction.
Abstract Obesity is a global pandemic associated with macro- and microvascular endothelial dysfunction. Microvascular endothelial dysfunction has recently emerged as a significant risk factor for the development of cognitive impairment. In this review, we present evidence from clinical and preclinical studies supporting a role for obesity in cognitive impairment. Next, we discuss how obesity-related hyperinsulinemia/insulin resistance, systemic inflammation, and gut dysbiosis lead to cognitive impairment through induction of endothelial dysfunction and disruption of the blood brain barrier. Finally, we outline the...
Source: Neurobiology of Disease - August 24, 2019 Category: Neurology Authors: Jones Buie JN, Watson LS, Smith CJ, Sims-Robinson C Tags: Neurobiol Dis Source Type: research

Rational polytherapy in the treatment of cholinergic seizures.
Abstract The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soma...
Source: Neurobiology of Disease - August 24, 2019 Category: Neurology Authors: Niquet J, Lumley L, Baldwin R, Rossetti F, Suchomelova L, Naylor D, Estrada IBF, Wasterlain CG Tags: Neurobiol Dis Source Type: research

Altered microglia and neurovasculature in the Alzheimer's disease cerebellum.
This study aims to investigate neuropathology and AD-related molecular changes within the neocerebellum using post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was conducted on neocerebellar paraffin-embedded TMAs from 24 AD and 24 matched control cases, and free-floating neocerebellar sections from 6 AD and 6 controls. Immunoreactivity was compared between control and AD groups for neuropathological hallmarks (amyloid-β, tau, ubiquitin), Purkinje cells (calbindin), microglia (IBA1, HLA-DR), astrocytes (GFAP) basement-membrane associated molecules (fibronectin, collagen IV), endothelial cells (CD...
Source: Neurobiology of Disease - August 24, 2019 Category: Neurology Authors: Singh-Bains MK, Linke V, Austria MDR, Tan AYS, Scotter EL, Mehrabi NF, Faull RLM, Dragunow M Tags: Neurobiol Dis Source Type: research

Finding intestinal fortitude: Integrating the microbiome into a holistic view of depression mechanisms, treatment, and resilience.
Abstract Depression affects at least 322 million people globally, or approximately 4.4% of the world's population. While the earnestness of researchers and clinicians to understand and treat depression is not waning, the number of individuals suffering from depression continues to increase over and above the rate of global population growth. There is a sincere need for a paradigm shift. Research in the past decade is beginning to take a more holistic approach to understanding depression etiology and treatment, integrating multiple body systems into whole-body conceptualizations of this mental health affliction. Ev...
Source: Neurobiology of Disease - August 24, 2019 Category: Neurology Authors: Flux MC, Lowry CA Tags: Neurobiol Dis Source Type: research

Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment.
Abstract Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Nav1.1. The syndrome is characterized by age-related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Nav1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Schuster J, Laan L, Klar J, Jin Z, Huss M, Korol S, Noraddin FH, Sobol M, Birnir B, Dahl N Tags: Neurobiol Dis Source Type: research

RANTES-induced invasion of Th17 cells into substantia nigra potentiates dopaminergic cell loss in MPTP mouse model of Parkinson's disease.
Abstract Although Parkinson's disease (PD) is a progressive neurodegenerative disease, the disease does not progress or persist in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, the most common animal model of PD. Recently, we have described that supplementation of regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine known to drive infiltration of T cells, induces persistent nigrostriatal pathology in MPTP mouse model. However, which particular T cell subsets are recruited to the substantia nigra (SN) by RANTES is not known. Here, by adoptive transfer of different s...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Dutta D, Kundu M, Mondal S, Roy A, Ruehl S, Hall DA, Pahan K Tags: Neurobiol Dis Source Type: research

Dystonia and levodopa-induced dyskinesias in Parkinson's disease: Is there a connection?
Abstract Dystonia and levodopa-induced dyskinesia (LID) are both hyperkinetic movement disorders. Dystonia arises most often spontaneously, although it may be seen after stroke, injury, or as a result of genetic causes. LID is associated with Parkinson's disease (PD), emerging as a consequence of chronic therapy with levodopa, and may be either dystonic or choreiform. LID and dystonia share important phenomenological properties and mechanisms. Both LID and dystonia are generated by an integrated circuit involving the cortex, basal ganglia, thalamus and cerebellum. They also share dysregulation of striatal choliner...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Calabresi P, Standaert DG Tags: Neurobiol Dis Source Type: research

Perturbations in RhoA signalling cause altered migration and impaired neuritogenesis in human iPSC-derived neural cells with PARK2 mutation.
R, Meyer M Abstract Mutations in parkin, encoded by the PARK2 gene, causes early-onset familial Parkinson's disease (PD), but dysfunctional parkin has also been implicated in sporadic PD. By combining human isogenic induced pluripotent stem cells (iPSCs) with and without PARK2 knockout (KO) and a novel large-scale mass spectrometry based proteomics and post-translational modification (PTM)-omics approach, we have mapped changes in protein profiles and PTMs caused by parkin deficiency in neurons. Our study identifies changes to several proteins previously shown to be dysregulated in brains of sporadic PD patients. ...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Bogetofte H, Jensen P, Okarmus J, Schmidt SI, Agger M, Ryding M, Nørregaard P, Fenger C, Zeng X, Graakjær J, Ryan BJ, Wade-Martins R, Larsen MR, Meyer M Tags: Neurobiol Dis Source Type: research

Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo.
Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. Neurobiol Dis. 2019 Aug 21;:104582 Authors: Schofield DJ, Irving L, Calo L, Bogstedt A, Rees G, Nuccitelli A, Narwal R, Petrone M, Roberts J, Brown L, Cusdin F, Dosanjh B, Lloyd C, Dobson C, Gurrell I, Fraser G, McFarlane M, Rockenstein E, Spencer B, Masliah E, Spillantini MG, Tan K, Billinton A, Vaughan T, Chessell I, Perkinton MS Abstract There are no approved drug therapies that can prevent or slow the...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Schofield DJ, Irving L, Calo L, Bogstedt A, Rees G, Nuccitelli A, Narwal R, Petrone M, Roberts J, Brown L, Cusdin F, Dosanjh B, Lloyd C, Dobson C, Gurrell I, Fraser G, McFarlane M, Rockenstein E, Spencer B, Masliah E, Spillantini MG, Tan K, Billinton A, V Tags: Neurobiol Dis Source Type: research

Smooth muscle cell-specific knockout of FBW7 exacerbates intracranial atherosclerotic stenosis.
Abstract Intracranial atherosclerotic stenosis (ICAS), the most common cause of stroke worldwide, is associated with high risk of recurrent ischemic stroke. F-box and WD repeat domain containing protein 7 (FBW7), an ubiquitin E3 ligase, is recently suggested to be involved in atherogenesis. However, whether FBW7 affects cerebrovascular remodeling during ICAS remains unknowns. We found that the expression of FBW7 was decreased in mouse brain microvessels from high-fat diet (HFD)-fed atherosclerotic mice. The reduced FBW7 expression was negatively associated with the remodeling of middle cerebral artery (MCA). Speci...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Shen Y, Chen X, Chi C, Wang H, Xue J, Su D, Wang H, Li M, Liu B, Dong Q Tags: Neurobiol Dis Source Type: research

HAP1 is an in vivo UBE3A target that augments autophagy in a mouse model of Angelman syndrome.
Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal mutation and paternal imprinting of the gene encoding UBE3A, an E3 ubiquitin ligase. Although several potential target proteins of UBE3A have been reported, how these proteins regulate neuronal development remains unclear. We performed a large-scale quantitative proteomic analysis using stable-isotope labeling of amino acids in mammals (SILAM) in mice with maternal Ube3a mutation. We identified huntingtin (Htt)-associated protein (HAP1), a protein that is involved in Huntington's disease (HD), as a new target of UBE3A. We de...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Wang T, Wang J, Wang J, Mao L, Tang B, Vanderklish PW, Liao X, Xiong ZQ, Liao L Tags: Neurobiol Dis Source Type: research

Emerging roles for the intestinal microbiome in epilepsy.
Abstract The gut microbiome is emerging as a key regulator of brain function and behavior and is associated with symptoms of several neurological disorders. There is emerging evidence that alterations in the gut microbiota are seen in epilepsy and in response to seizure interventions. In this review, we highlight recent studies reporting that individuals with refractory epilepsy exhibit altered composition of the gut microbiota. We further discuss antibiotic treatment and infection as microbiome-related factors that influence seizure susceptibility in humans and animal models. In addition, we evaluate how the micr...
Source: Neurobiology of Disease - August 21, 2019 Category: Neurology Authors: Lum GR, Olson CA, Hsiao EY Tags: Neurobiol Dis Source Type: research

Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition.
Abstract Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough resi...
Source: Neurobiology of Disease - August 16, 2019 Category: Neurology Authors: Arystarkhova E, Haq IU, Luebbert T, Mochel F, Saunders-Pullman R, Bressman SB, Feschenko P, Salazar C, Cook JF, Demarest S, Brashear A, Ozelius LJ, Sweadner KJ Tags: Neurobiol Dis Source Type: research

Leptin deficiency reverses high metabolic state and weight loss without affecting central pathology in the R6/2 mouse model of Huntington's disease.
In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type littermates. The increased body weight was accompanied by low energy expenditure, illustrated by a reduction in respiratory exchange rate. Leptin- deficient R6/2 mice had large white adipocytes with white adipocyte gene expression characteristics, in contrast to white adipose tissue in R6/2 mice, where white adipose tissue showed signs of browning. Leptin-deficient R6/2 mice did not exhibit improved neuropathological measures. Our results indicate th...
Source: Neurobiology of Disease - August 13, 2019 Category: Neurology Authors: Sjögren M, Soylu-Kucharz R, Dandunna U, Stan TL, Cavalera M, Sandelius Å, Zetterberg H, Björkqvist M Tags: Neurobiol Dis Source Type: research

Antibody-based therapies for Huntington's disease: current status and future directions.
Abstract The types of treatments and interventions being developed for chronic neurodegenerative disorders have expanded considerably in recent years. In addition to the variety of targets being pursued, strategies have moved from symptom management to more directed disease-modifying approaches. Among them are antibody-based therapies, which are not only being evaluated for a range of tauopathies and synucleinopathies, but are also emerging as a potential application for monogenic disorders of the central nervous system (CNS), including Huntington's disease (HD). Despite the excitement around the early trial data ...
Source: Neurobiology of Disease - August 6, 2019 Category: Neurology Authors: Denis HL, David LS, Cicchetti F Tags: Neurobiol Dis Source Type: research

Neurotrophin receptor p75 mediates amyloid β-induced tau pathology.
Neurotrophin receptor p75 mediates amyloid β-induced tau pathology. Neurobiol Dis. 2019 Aug 05;:104567 Authors: Shen LL, Li WW, Xu YL, Gao SH, Xu MY, Bu XL, Liu YH, Wang J, Zhu J, Zeng F, Yao XQ, Gao CY, Xu ZQ, Zhou XF, Wang YJ Abstract Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aβ) accumulation. However, the mechanism by which Aβ induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for A...
Source: Neurobiology of Disease - August 5, 2019 Category: Neurology Authors: Shen LL, Li WW, Xu YL, Gao SH, Xu MY, Bu XL, Liu YH, Wang J, Zhu J, Zeng F, Yao XQ, Gao CY, Xu ZQ, Zhou XF, Wang YJ Tags: Neurobiol Dis Source Type: research

Glucocorticoid receptors modulate dendritic spine plasticity and microglia activity in an animal model of Alzheimer's disease.
In this study, we evaluated, using combined Golgi Cox and immunofluorescence techniques, the role of GR agonists and antagonists on dendritic spine plasticity and microglia activation in hippocampus of 3xTg-AD mice. We found that dexamethasone, an agonist of GRs, was able to significantly reduce dendritic spine density and induced proliferation and activation of microglia in CA1 region of hippocampus of 3xTg-AD mice at 6 and 10 months of age. On the contrary, the treatment with mifepristone, an antagonist of GRs, strongly enhanced dendritic spine density, decreased microglia density and improved the behavioural performan...
Source: Neurobiology of Disease - August 5, 2019 Category: Neurology Authors: Pedrazzoli M, Losurdo M, Paolone G, Medelin M, Jaupaj L, Cisterna B, Slanzi A, Malatesta M, Coco S, Buffelli M Tags: Neurobiol Dis Source Type: research

Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine.
Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol Dis. 2019 Aug 05;:104570 Authors: Gonçalves FQ, Lopes JP, Silva HB, Lemos C, Silva AC, Gonçalves N, Tomé ÂR, Ferreira SG, Canas PM, Rial D, Agostinho P, Cunha RA Abstract Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release...
Source: Neurobiology of Disease - August 5, 2019 Category: Neurology Authors: Gonçalves FQ, Lopes JP, Silva HB, Lemos C, Silva AC, Gonçalves N, Tomé ÂR, Ferreira SG, Canas PM, Rial D, Agostinho P, Cunha RA Tags: Neurobiol Dis Source Type: research

5'UTR-mediated regulation of Ataxin-1 expression.
Abstract Expression of mutant Ataxin-1 with an abnormally expanded polyglutamine domain is necessary for the onset and progression of spinocerebellar ataxia type 1 (SCA1). Understanding how Ataxin-1 expression is regulated in the human brain could inspire novel molecular therapies for this fatal, dominantly inherited neurodegenerative disease. Previous studies have shown that the ATXN1 3'UTR plays a key role in regulating the Ataxin-1 cellular pool via diverse post-transcriptional mechanisms. Here we show that elements within the ATXN1 5'UTR also participate in the regulation of Ataxin-1 expression. PCR and PacBio...
Source: Neurobiology of Disease - August 2, 2019 Category: Neurology Authors: Manek R, Nelson T, Tseng E, Rodriguez-Lebron E Tags: Neurobiol Dis Source Type: research

Examining the relationship between astrocyte dysfunction and neurodegeneration in ALS using hiPSCs.
Abstract Amyotrophic lateral sclerosis (ALS) is a complex and fatal neurodegenerative disease for which the causes of disease onset and progression remain unclear. Recent advances in human induced pluripotent stem cell (hiPSC)-based models permit the study of the genetic factors associated with ALS in patient-derived neural cell types, including motor neurons and glia. While astrocyte dysfunction has traditionally been thought to exacerbate disease progression, astrocytic dysfunction may play a more direct role in disease initiation and progression. Such non-cell autonomous mechanisms expand the potential targets ...
Source: Neurobiology of Disease - August 2, 2019 Category: Neurology Authors: Halpern M, Brennand KJ, Gregory J Tags: Neurobiol Dis Source Type: research

"Depressed" caudate and ventral striatum dopamine transporter availability in de novo Depressed Parkinson's disease.
This study investigated whether there exist distinctive patterns of presynaptic monoamine transporter densities in the basal ganglia depending on the degree of depression in patients with PD. A total of 123 early and drug-naïve PD patients were enrolled. Their affective status was evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS), and subjects were subgrouped into one of the following three groups according to their MADRS scores: no depression, mild depression, and moderate-to-severe depression. All patients underwent positron emission tomography (PET) using 18F-N-(3-fluoropropyl)-2beta-carbon e...
Source: Neurobiology of Disease - August 1, 2019 Category: Neurology Authors: Yoo SW, Oh YS, Hwang EJ, Ryu DW, Lee KS, Lyoo CH, Kim JS Tags: Neurobiol Dis Source Type: research

Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation.
Abstract Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial m...
Source: Neurobiology of Disease - July 31, 2019 Category: Neurology Authors: Sen NE, Canet-Pons J, Halbach MV, Arsovic A, Pilatus U, Chae WH, Kaya ZE, Seidel K, Rollmann E, Mittelbronn M, Meierhofer D, De Zeeuw CI, Bosman LWJ, Gispert S, Auburger G Tags: Neurobiol Dis Source Type: research

Stem cell factor and granulocyte colony-stimulating factor promote brain repair and improve cognitive function through VEGF-A in a mouse model of CADASIL.
This study provides novel insight into the involvement of VEGF/VEGF-A in the pathogenesis of CADASIL and sheds light on the mechanism underlying the SCF+G-CSF-enhanced brain repair in CADASIL. PMID: 31376480 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - July 31, 2019 Category: Neurology Authors: Ping S, Qiu X, Kyle M, Hughes K, Longo J, Zhao LR Tags: Neurobiol Dis Source Type: research

Preface: Discovery and development of better medical countermeasures for chemical threats targeting the nervous system.
e; SL PMID: 31374245 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - July 30, 2019 Category: Neurology Authors: Jett DA, Galanopoulou AS, Moshé SL Tags: Neurobiol Dis Source Type: research

The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease.
Abstract Our understanding of the molecular mechanisms underlying differential vulnerability of substantia nigra dopamine neurons in Parkinson's disease (PD) remains limited, and previous therapeutic efforts targeting rodent nigral neurons have not been successfully translated to humans. However, recent emergence of induced pluripotent stem cell technology has highlighted some fundamental differences between human and rodent midbrain dopamine neurons that may at least in part explain relative resistance of rodent neurons to degeneration in genetic models of PD. Using GBA1-linked PD as an example, we discuss cellul...
Source: Neurobiology of Disease - July 25, 2019 Category: Neurology Authors: Burbulla LF, Krainc D Tags: Neurobiol Dis Source Type: research

Metabolic interventions in Autism Spectrum Disorder.
Abstract Metabolic interventions including special diets and supplements are commonly used in Autism Spectrum Disorder (ASD). Yet little is known about how these interventions, typically initiated by caregivers, may affect metabolic function or the core symptoms of ASD. This review examines possible direct and indirect roles for metabolism in the core symptoms of ASD as well as evidence for metabolic dysfunction and nutritional deficiencies. We also discuss some of the most popular diets and supplements used in our patient population and suggest strategies for discussing the utility of these interventions with pat...
Source: Neurobiology of Disease - July 24, 2019 Category: Neurology Authors: Mierau SB, Neumeyer AM Tags: Neurobiol Dis Source Type: research

Periodic dietary restriction ameliorates amyloid pathology and cognitive impairment in PDAPP-J20 mice: Potential implication of glial autophagy.
uis J Abstract Dietary restriction promotes cell regeneration and stress resistance in multiple models of human diseases. One of the conditions that could potentially benefit from this strategy is Alzheimer's disease, a chronic, progressive and prevalent neurodegenerative disease. Although there are no effective pharmacological treatments for this pathology, lifestyle interventions could play therapeutic roles. Our objectives were 1) to evaluate the effects of dietary restriction on cognition, hippocampal amyloid deposition, adult neurogenesis and glial reactivity and autophagy in a mouse model of familial Alzheim...
Source: Neurobiology of Disease - July 24, 2019 Category: Neurology Authors: Gregosa A, Vinuesa Á, Todero MF, Pomilio C, Rossi SP, Bentivegna M, Presa J, Wenker S, Saravia F, Beauquis J Tags: Neurobiol Dis Source Type: research

Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration.
Dynamic behaviors of α-synuclein and tau in the cellular context: New mechanistic insights and therapeutic opportunities in neurodegeneration. Neurobiol Dis. 2019 Jul 24;:104543 Authors: Yeboah F, Kim TE, Bill A, Dettmer U Abstract α-Synuclein (αS) and tau have a lot in common. Dyshomeostasis and aggregation of both proteins is central in the pathogenesis of neurodegenerative diseases: Parkinson's disease, dementia with Lewy bodies, multi-system atrophy and other 'synucleinopathies' in the case of αS; Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy ...
Source: Neurobiology of Disease - July 24, 2019 Category: Neurology Authors: Yeboah F, Kim TE, Bill A, Dettmer U Tags: Neurobiol Dis Source Type: research

Brain-derived neurotrophic factor (BDNF) and TrkB hippocampal gene expression are putative predictors of neuritic plaque and neurofibrillary tangle pathology.
DISCUSSION: Results indicate that BDNF and TrkB dysregulation contribute to AD neuropathology, most notably hippocampal NPs and NFTs. These data suggest attenuating BDNF/TrkB signaling deficits either at the level of BDNF, TrkB, or downstream of TrkB signaling may abrogate NPs and/or NFTs. PMID: 31349032 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - July 23, 2019 Category: Neurology Authors: Ginsberg SD, Malek-Ahmadi MH, Alldred MJ, Chen Y, Chen K, Chao MV, Counts SE, Mufson EJ Tags: Neurobiol Dis Source Type: research

The effects of insulin and insulin-like growth factor I on amyloid precursor protein phosphorylation in in vitro and in vivo models of Alzheimer's disease.
In this report, we therefore investigated the mechanisms underlying the effects of insulin and IGF-I on AD-associated pathology in the context of IR, with particular emphasis on phosphorylation of amyloid precursor protein (APP), a key step in promoting amyloid plaque formation in AD. Both insulin and IGF-I decreased APP phosphorylation in cultured primary cortical neurons, supporting their therapeutic use in AD. Induction of IR blocked the beneficial effect of insulin and reduced the effect of IGF-I on APP dephosphorylation. These effects were mediated by the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt) pa...
Source: Neurobiology of Disease - July 23, 2019 Category: Neurology Authors: Kim B, Elzinga SE, Henn RE, McGinley LM, Feldman EL Tags: Neurobiol Dis Source Type: research