Enhancer of Zeste 1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia.
CONCLUSIONS: EZH1 is dysregulated in schizophrenia, sensitive to antipsychotic medications, and a brain-enriched miR-132 target that controls neurobehavioral phenotypes. PMID: 30099093 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - August 9, 2018 Category: Neurology Authors: Johnstone AL, O'Reilly JJ, Patel AJ, Guo Z, Andrade NS, Magistri M, Nathanson L, Esanov R, Miller BH, Turecki G, Brothers SP, Zeier Z, Wahlestedt C Tags: Neurobiol Dis Source Type: research

Targeting neurodegeneration to prevent post-traumatic epilepsy.
Abstract In the quest for developing new therapeutic targets for post-traumatic epilepsies (PTE), identifying mechanisms relevant to development and progression of disease is critical. A growing body of literature suggests involvement of neurodegenerative mechanisms in the pathophysiology of acquired epilepsies, including following traumatic brain injury (TBI). In this review, we discuss the potential of some of these mechanisms to be targets for the development of a therapy against PTE. PMID: 30099094 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - August 9, 2018 Category: Neurology Authors: Ali I, Silva J, Liu S, Shultz S, Kwan P, Jones N, O'Brien TJ Tags: Neurobiol Dis Source Type: research

Regenerating islet-derived 1 α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies.
Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies. Neurobiol Dis. 2018 Aug 06;: Authors: Moussaed M, Huc-Brandt S, Cubedo N, Silhol M, Murat S, Lebart MC, Kovacs G, Verdier JM, Trousse F, Rossel M, Marcilhac A Abstract REG-1α, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1α is expressed also in the brain where it has different functio...
Source: Neurobiology of Disease - August 6, 2018 Category: Neurology Authors: Moussaed M, Huc-Brandt S, Cubedo N, Silhol M, Murat S, Lebart MC, Kovacs G, Verdier JM, Trousse F, Rossel M, Marcilhac A Tags: Neurobiol Dis Source Type: research

Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases.
ger V Abstract Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Se...
Source: Neurobiology of Disease - August 6, 2018 Category: Neurology Authors: Genin EC, Bannwarth S, Lespinasse F, Ortega-Vila B, Fragaki K, Itoh K, Villa E, Lacas-Gervais S, Jokela M, Auranen M, Ylikallio E, Mauri-Crouzet A, Tyynismaa H, Vihola A, Augé G, Cochaud C, Sesaki H, Ricci JE, Udd B, Vives-Bauza C, Paquis-Flucklinger V Tags: Neurobiol Dis Source Type: research

Alpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function.
Outeiro TF Abstract Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, C...
Source: Neurobiology of Disease - August 6, 2018 Category: Neurology Authors: Paiva I, Jain G, Lázaro DF, Jerčić KG, Hentrich T, Kerimoglu C, Pinho R, Szegő ÈM, Burkhardt S, Capece V, Halder R, Islam R, Xylaki M, Caldi Gomes LA, Roser AE, Lingor P, Schulze-Hentrich JM, Borovečki F, Fischer A, Outeiro TF Tags: Neurobiol Dis Source Type: research

Differences in structural and functional networks between young adult and aged rat brains before and after stroke lesion simulations.
Abstract Neural network changes during aging may contribute to vulnerability and resilience to brain lesions in age-related neurological disorders, such as stroke. However, the relationship between age-related neural network features and stroke outcome is unknown. Therefore, we assessed structural and functional network status in young adult and aged rat brain, and measured the effects of simulated stroke lesions. Eleven rats underwent diffusion-weighted MRI and resting-state functional MRI at young adult age (post-natal day 88) and old age (between post-natal day 760 and 880). Structural and functional brain netw...
Source: Neurobiology of Disease - August 4, 2018 Category: Neurology Authors: Straathof M, Sinke MRT, van der Toorn A, Weerheim PL, Otte WM, Dijkhuizen RM Tags: Neurobiol Dis Source Type: research

Spike discharge characteristic of the caudal mesencephalic reticular formation and pedunculopontine nucleus in MPTP-induced primate model of Parkinson disease.
e;s S Abstract The pedunculopontine nucleus (PPN) included in the caudal mesencephalic reticular formation (cMRF) plays a key role in the control of locomotion and wake state. Regarding its involvement in the neurodegenerative process observed in Parkinson disease (PD), deep brain stimulation of the PPN was proposed to treat levodopa-resistant gait disorders. However, the precise role of the cMRF in the pathophysiology of PD, particularly in freezing of gait and other non-motor symptoms is still not clear. Here, using micro electrode recording (MER) in 2 primates, we show that dopamine depletion did not alter the ...
Source: Neurobiology of Disease - August 4, 2018 Category: Neurology Authors: Goetz L, Piallat B, Bhattacharjee M, Mathieu H, David O, Chabardès S Tags: Neurobiol Dis Source Type: research

GlialCAM/MLC1 modulates LRRC8/VRAC currents in an indirect manner: Implications for megalencephalic leukoencephalopathy.
osini E, Gasull X, Estévez R Abstract Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes. Previous work indicated that chloride currents mediated by the volume-regulated anion channel (VRAC) and ClC-2 channels were affected in astrocytes deficient in either Mlc1 or Glialcam. ClC-2 forms a ternary complex with GlialCAM and MLC1. LRRC8 proteins have been identified recently as the molecular components of VRAC, but the relationship between MLC and LRRC8 proteins is unknown. Here, we first demonstrate that LRRC8 ...
Source: Neurobiology of Disease - August 1, 2018 Category: Neurology Authors: Elorza-Vidal X, Sirisi S, Gaitán-Peñas H, Pérez-Rius C, Alonso-Gardón M, Armand-Ugón M, Lanciotti A, Brignone MS, Prat E, Nunes V, Ambrosini E, Gasull X, Estévez R Tags: Neurobiol Dis Source Type: research

A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF- α and IL-6 in an iPSC-based blood-brain barrier model.
A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF-α and IL-6 in an iPSC-based blood-brain barrier model. Neurobiol Dis. 2018 Jul 31;: Authors: Mantle JL, Lee KH Abstract Inflammation can be a risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and may also contribute to the progression of AD. Here, we sought to understand how inflammation affects the properties of the brain microvascular endothelial cells (BMECs) that compose the blood-brain barrier (BBB), which is impaired in AD. A fully human in vitro BBB model wi...
Source: Neurobiology of Disease - July 31, 2018 Category: Neurology Authors: Mantle JL, Lee KH Tags: Neurobiol Dis Source Type: research

Novel E815K knock-in mouse model of alternating hemiplegia of childhood.
Abstract De novo mutations causing dysfunction of the ATP1A3 gene, which encodes the α3 subunit of Na+/K+-ATPase pump expressed in neurons, result in alternating hemiplegia of childhood (AHC). AHC manifests as paroxysmal episodes of hemiplegia, dystonia, behavioral abnormalities, and seizures. The first aim of this study was to characterize a novel knock-in mouse model (Atp1a3E815K+/-, Matoub, Matb+/-) containing the E815K mutation of the Atp1a3 gene recognized as causing the most severe and second most common phenotype of AHC with increased morbidity and mortality as compared to other mutations. The second ...
Source: Neurobiology of Disease - July 30, 2018 Category: Neurology Authors: Helseth AR, Hunanyan AS, Adil S, Linabarger M, Sachdev M, Abdelnour E, Arehart E, Szabo M, Richardson J, Wetsel WC, Hochgeschwender U, Mikati MA Tags: Neurobiol Dis Source Type: research

Affective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy.
Abstract Survivors of traumatic brain injury (TBI) often develop chronic neurological, neurocognitive, psychological, and psychosocial deficits that can have a profound impact on an individual's wellbeing and quality of life. TBI is also a common cause of acquired epilepsy, which is itself associated with significant behavioral morbidity. This review considers the clinical and preclinical evidence that post-traumatic epilepsy (PTE) acts as a 'second-hit' insult to worsen chronic behavioral outcomes for brain-injured patients, across the domains of emotional, cognitive, and psychosocial functioning. Surprisingly, f...
Source: Neurobiology of Disease - July 27, 2018 Category: Neurology Authors: Semple BD, Zamani A, Rayner G, Shultz SR, Jones NC Tags: Neurobiol Dis Source Type: research

Large-conductance Ca2+-activated potassium channels are potently involved in the inverse neurovascular response to spreading depolarization.
F, Krizbai IA, Farkas E Abstract Recurrent spreading depolarizations occur in the cerebral cortex from minutes up to weeks following acute brain injury. Clinical evidence suggests that the immediate reduction of cerebral blood flow in response to spreading depolarization importantly contributes to lesion progression as the wave propagates over vulnerable tissue zones, characterized by potassium concentration already elevated prior to the passage of spreading depolarization. Here we demonstrate with two-photon microscopy in anesthetized mice that initial vasoconstriction in response to SD triggered experimentally w...
Source: Neurobiology of Disease - July 24, 2018 Category: Neurology Authors: Menyhárt Á, Farkas AE, Varga DP, Frank R, Tóth R, Bálint AR, Makra P, Dreier JP, Bari F, Krizbai IA, Farkas E Tags: Neurobiol Dis Source Type: research

Microstructural alterations of cortical and deep gray matter over a season of high school football revealed by diffusion kurtosis imaging.
CONCLUSION: Microstructural alterations over the season and correlations with head impacts were captured by DKI metrics, which suggested that DKI imaging of gray matter may yield valuable biomarkers for evaluating brain injuries associated with subconcussive head impact. Findings in frontal cortical gray matter also indicated that contrecoup injury rather than coup injury might be the dominant mechanism underlying the observed microstructural alterations. ADVANCES IN KNOWLEDGE: Significant microstructural changes, as reflected by DKI metrics, in cortical gray matter such as the rostral middle frontal cortices, and in ...
Source: Neurobiology of Disease - July 23, 2018 Category: Neurology Authors: Gong NJ, Kuzminski S, Clark M, Fraser M, Sundman M, Guskiewicz K, Petrella JR, Liu C Tags: Neurobiol Dis Source Type: research

Leucine-rich repeat kinase 2 aggravates secondary brain injury induced by intracerebral hemorrhage in rats by regulating the P38 MAPK/Drosha pathway.
In this study, an ICH model was induced by injecting autologous whole blood into the right basal ganglia of adult rats. Meanwhile, primary rat cortical neurons treated with Oxyhemoglobin (OxyHb) were used as an in vitro ICH model. Protein levels of LRRK2 increased significantly in brain tissues after ICH. Upregulation of LRRK2 by genetic overexpression augmented inflammatory responses, behavioral and cognitive dysfunction, brain edema, blood-brain barrier (BBB) injury, and cell death involved in SBI following ICH. Downregulation of LRRK2 by GNE7915 (a specific chemical inhibitor of LRRK2) and genetic knockdown yielded oppo...
Source: Neurobiology of Disease - July 23, 2018 Category: Neurology Authors: Cao J, Zhuang Y, Zhang J, Zhang Z, Yuan S, Zhang P, Li H, Li X, Shen H, Wang Z, Chen G Tags: Neurobiol Dis Source Type: research

Discovery of a CLN7 model of Batten disease in non-human primates.
Abstract We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7-/-). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7-/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-yea...
Source: Neurobiology of Disease - July 23, 2018 Category: Neurology Authors: McBride JL, Neuringer M, Ferguson B, Kohama SG, Tagge IJ, Zweig R, Renner LM, McGill TJ, Stoddard J, Peterson S, Su W, Sherman LS, Domire JS, Ducore RM, Colgin LM, Lewis AD Tags: Neurobiol Dis Source Type: research

The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol.
Staba R, Toga A, Willyerd FA, Zimmermann L, Yam E, Martinez S, Real C, Engel J, EpiBioS4Rx Study Group, Agoston D, Au A, Bell MJ, Bleck Thomas P, Branch C, Buitrago Blanco M, Bullock R, Burrows BT, Claassen J, Clarke R, Cloyd J, Coles L, Crawford K, Diaz-Arrastia R, Duncan D, Ellingson B, Engel J, Foreman B, Galanopoulou A, Gilmore E, Olli G, Harris N, Hartings J, Lawrence H, Hunn M, Jette N, Johnston L, Jones N, Kanner A, McArthur D, Monti M, Morokoff A, Moshe S, Mowrey W, O'Brien T, O'Phelan K, Pitkanen A, Raman R, Robertson C, Rosenthal E, Shultz S, Snutch T, Staba R, Toga A, Van Horn J, Vespa P, Willyerd F, Zimmermann...
Source: Neurobiology of Disease - July 23, 2018 Category: Neurology Authors: Vespa PM, Shrestha V, Abend N, Agoston D, Au A, Bell MJ, Bleck TP, Blanco MB, Claassen J, Diaz-Arrastia R, Duncan D, Ellingson B, Foreman B, Gilmore EJ, Hirsch L, Hunn M, Kamnaksh A, McArthur D, Morokoff A, O'Brien T, O'Phelan K, Robertson CL, Rosenthal E Tags: Neurobiol Dis Source Type: research

Mechanisms of demyelination and remyelination in the young and aged brain following white matter stroke.
Abstract Subcortical white matter stroke (WMS) accounts for 25% of all incidences of stroke and results in severe motor and cognitive disability. WMS stands as the second leading cause of dementia and is immensely prevalent in older adults. In a startlingly statistic, a majority of human beings will present WMS by 80 years of age. Early ischemic lesions produced by WMS are asymptomatic and termed "silent strokes". WMS is, however, progressive with both the size of the lesions and their distribution, increasing as patients age. Pathological analyses in both postmortem human tissue samples and mouse mode...
Source: Neurobiology of Disease - July 19, 2018 Category: Neurology Authors: Marin MA, Carmichael ST Tags: Neurobiol Dis Source Type: research

Selective vulnerability of hippocampal interneurons to graded traumatic brain injury.
Abstract Traumatic brain injury is a major risk factor for many long-term mental health problems. Although underlying mechanisms likely involve compromised inhibition, little is known about how individual subpopulations of interneurons are affected by neurotrauma. Here we report long-term loss of hippocampal interneurons following controlled cortical impact (CCI) injury in young-adult mice, a model of focal cortical contusion injury in humans. Brain injured mice displayed subfield and cell-type specific decreases in interneurons 30 days after impact depths of 0.5 mm and 1.0 mm, and increasing the depth of im...
Source: Neurobiology of Disease - July 19, 2018 Category: Neurology Authors: Frankowski JC, Kim YJ, Hunt RF Tags: Neurobiol Dis Source Type: research

Cypin: A novel target for traumatic brain injury.
Abstract Cytosolic PSD-95 interactor (cypin), the primary guanine deaminase in the brain, plays key roles in shaping neuronal circuits and regulating neuronal survival. Despite this pervasive role in neuronal function, the ability for cypin activity to affect recovery from acute brain injury is unknown. A key barrier in identifying the role of cypin in neurological recovery is the absence of pharmacological tools to manipulate cypin activity in vivo. Here, we use a small molecule screen to identify two activators and one inhibitor of cypin's guanine deaminase activity. The primary screen identified compounds that ...
Source: Neurobiology of Disease - July 18, 2018 Category: Neurology Authors: Swiatkowski P, Sewell E, Sweet ES, Dickson S, Swanson RA, McEwan SA, Cuccolo N, McDonnell ME, Patel MV, Varghese N, Morrison B, Reitz AB, Meaney DF, Firestein BL Tags: Neurobiol Dis Source Type: research

Effects of aging, hypertension and diabetes on the mouse brain and heart vasculomes.
Abstract The emerging concept of the vasculome suggests that microvessels contribute to function and dysfunction in every organ. In the brain, aging and comorbidities such as hypertension and diabetes significantly influence a wide variety of neurodegenerative and cerebrovascular disorders, but the underlying mechanisms are complex and remain to be fully elucidated. Here, we hypothesize that aging, hypertension and diabetes perturb gene networks in the vasculome. Microvascular endothelial cells were isolated from mouse brain and heart, and their transcriptomes were profiled with microarrays. For aging, we compared...
Source: Neurobiology of Disease - July 18, 2018 Category: Neurology Authors: Guo S, Deng W, Xing C, Zhou Y, Ning M, Lo EH Tags: Neurobiol Dis Source Type: research

Applying participatory action research in traumatic brain injury studies to prevent post-traumatic epilepsy.
gement Core Abstract The increased focus on stakeholder engagement in determining the aims, design, conduct of research and dissemination of results is substantially changing the biomedical research paradigm. In this era of patient-centered care, incorporating participatory action research methodology into large-scale multi-center studies is essential. The adoption of community engagement facilitates meaningful contribution to the design and implementation of clinical studies. Consequently, encouraging citizen participation and involving key organizations may guide the effective development of future clinical rese...
Source: Neurobiology of Disease - July 18, 2018 Category: Neurology Authors: Correa DJ, Kwon CS, Connors S, Fureman B, Whittemore V, Jetté N, Mathern GW, Moshé SL, EpiBioS4Rx Public Engagement Core Tags: Neurobiol Dis Source Type: research

Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease.
In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces β-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb-/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb-/- mice, tremo...
Source: Neurobiology of Disease - July 17, 2018 Category: Neurology Authors: Ogawa Y, Furusawa E, Saitoh T, Sugimoto H, Omori T, Shimizu S, Kondo H, Yamazaki M, Sakuraba H, Oishi K Tags: Neurobiol Dis Source Type: research

Protein biomarkers of epileptogenicity after traumatic brain injury.
Abstract Traumatic brain injury (TBI) is a major risk factor for acquired epilepsy. Post-traumatic epilepsy (PTE) develops over time in up to 50% of patients with severe TBI. PTE is mostly unresponsive to traditional anti-seizure treatments suggesting distinct, injury-induced pathomechanisms in the development of this condition. Moderate and severe TBIs cause significant tissue damage, bleeding, neuron and glia death, as well as axonal, vascular, and metabolic abnormalities. These changes trigger a complex biological response aimed at curtailing the physical damage and restoring homeostasis and functionality. Alth...
Source: Neurobiology of Disease - July 17, 2018 Category: Neurology Authors: Agoston DV, Kamnaksh A Tags: Neurobiol Dis Source Type: research

Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases.
Abstract Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the co...
Source: Neurobiology of Disease - July 17, 2018 Category: Neurology Authors: Chu CT Tags: Neurobiol Dis Source Type: research

Breakdown of blood brain barrier as a mechanism of post-traumatic epilepsy.
Abstract Traumatic brain injury (TBI) accounts for approximately 16% of acute symptomatic seizures which usually occur in the first week after trauma. Children are at higher risk for post-traumatic seizures than adults. Post-traumatic seizures are a risk factor for delayed development of epilepsy. Delayed, chronic post-traumatic epilepsy is preceded by a silent period during which therapeutic interventions may arrest, revert or prevent epileptogenesis. A number of recent review articles summarize the most important features of post-traumatic seizures and epilepsy; this review will instead focus on the link between...
Source: Neurobiology of Disease - July 17, 2018 Category: Neurology Authors: Dadas A, Janigro D Tags: Neurobiol Dis Source Type: research

Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy.
Meissner WG Abstract Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with multiple system atrophy who were treated with deep brain stimulation (DBS) of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem a...
Source: Neurobiology of Disease - July 16, 2018 Category: Neurology Authors: López-Cuiña M, Fernagut PO, Canron MH, Vital A, Lannes B, De Paula AM, Streichenberger N, Guehl D, Damier P, Eusebio A, Houeto JL, Tison F, Tranchant C, Viallet F, Witjas T, Thobois S, Meissner WG Tags: Neurobiol Dis Source Type: research

D159 and S167 are protective residues in the prion protein from dog and horse, two prion-resistant animals.
Abstract Prion diseases are fatal neurodegenerative diseases caused by misfolding of the prion protein (PrP). These conditions affect humans and animals, including endemic forms in sheep and deer. Bovine, rodents, and many zoo mammals also developed prion diseases during the "mad-cow" epidemic in the 1980's. Interestingly, rabbits, horses, and dogs show unusual resistance to prion diseases, suggesting that specific sequence changes in the corresponding endogenous PrP prevents the accumulation of pathogenic conformations. In vitro misfolding assays and structural studies have identified S174, S167, and D1...
Source: Neurobiology of Disease - July 12, 2018 Category: Neurology Authors: Sanchez-Garcia J, Fernandez-Funez P Tags: Neurobiol Dis Source Type: research

Activation of cyclin D1 affects mitochondrial mass following traumatic brain injury.
Abstract Cell cycle activation has been associated with varying types of neurological disorders including brain injury. Cyclin D1 is a critical modulator of cell cycle activation and upregulation of Cyclin D1 in neurons contributes to the pathology associated with traumatic brain injury (TBI). Mitochondrial mass is a critical factor to maintain the mitochondrial function, and it can be regulated by different signaling cascades and transcription factors including NRF1. However, the underlying mechanism of how TBI leads to impairment of mitochondrial mass following TBI remains obscure. Our results indicate that augm...
Source: Neurobiology of Disease - July 12, 2018 Category: Neurology Authors: Saha P, Gupta R, Sen T, Sen N Tags: Neurobiol Dis Source Type: research

Astrocyte-derived Jagged-1 mitigates deleterious Notch signaling in amyotrophic lateral sclerosis.
Abstract Amyotrophic lateral sclerosis (ALS) is a late-onset devastating degenerative disease mainly affecting motor neurons. Motor neuron degeneration is accompanied and aggravated by oligodendroglial pathology and the presence of reactive astrocytes and microglia. We studied the role of the Notch signaling pathway in ALS, as it is implicated in several processes that may contribute to this disease, including axonal retraction, microgliosis, astrocytosis, oligodendrocyte precursor cell proliferation and differentiation, and cell death. We observed abnormal activation of the Notch signaling pathway in the spinal c...
Source: Neurobiology of Disease - July 12, 2018 Category: Neurology Authors: Annelies N, Nathan C, Lewandowski Sebastian A, Rik N, Thal Dietmar R, Pfrieger Frank W, John R, Philip VD, An Z, Den Bosch Ludo V, Wim R Tags: Neurobiol Dis Source Type: research

Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction.
Abstract BACKGROUND: Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS: Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5). RESULTS: Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic reso...
Source: Neurobiology of Disease - July 12, 2018 Category: Neurology Authors: Raz L, Bhaskar K, Weaver J, Marini S, Zhang Q, Thompson JF, Espinoza C, Iqbal S, Maphis NM, Weston L, Sillerud LO, Caprihan A, Pesko JC, Erhardt EB, Rosenberg GA Tags: Neurobiol Dis Source Type: research

Identification of an acute functional cross-talk between amyloid- β and glucocorticoid receptors at hippocampal excitatory synapses.
Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses. Neurobiol Dis. 2018 Jul 09;: Authors: Kootar S, Frandemiche ML, Dhib G, Mouska X, Lorivel T, Poupon-Silvestre G, Hunt H, Tronche F, Bethus I, Barik J, Marie H Abstract Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to ...
Source: Neurobiology of Disease - July 9, 2018 Category: Neurology Authors: Kootar S, Frandemiche ML, Dhib G, Mouska X, Lorivel T, Poupon-Silvestre G, Hunt H, Tronche F, Bethus I, Barik J, Marie H Tags: Neurobiol Dis Source Type: research

Poly-ubiquitin profile in Alzheimer disease brain.
Abstract Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory, reasoning and other cognitive functions. Pathologically, patients with AD are characterized by deposition of senile plaques (SPs), formed by β-amyloid (Aβ), and neurofibrillary tangles (NTFs) that consist of aggregated hyperphosphorylated tau protein. The accumulation of insoluble protein aggregates in AD brain can be associated with an impairment of degradative systems. This current study investigated if the disturbance of protein polyubiquitination is associated with AD neurodegeneration. By usi...
Source: Neurobiology of Disease - July 9, 2018 Category: Neurology Authors: Tramutola A, Triani F, Di Domenico F, Barone E, Cai J, Klein JB, Perluigi M, Allan Butterfield D Tags: Neurobiol Dis Source Type: research

Autophagy and mitophagy in ALS.
Abstract Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting thi...
Source: Neurobiology of Disease - July 5, 2018 Category: Neurology Authors: Evans CS, Holzbaur ELF Tags: Neurobiol Dis Source Type: research

Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice.
In this study, we for the first time provide evidence of reduced GPR40 signaling in the hippocampus and cortex which may be a critical underlying mechanism mediating cognitive deficits in diabesity (diabetes and obesity together). Specifically, we showed decreased GPR40 and brain-derived neurotrophic factor (BDNF) expression in the brain regions of high-fat-diet-induced obese and db/db mice. Next, we demonstrated that chronic treatment with docosahexaenoic acid (DHA) or the synthetic GPR40 agonist, GW9508, significantly alleviates cognitive functions in mice, which correlates with increased BDNF expression in the hippocamp...
Source: Neurobiology of Disease - July 5, 2018 Category: Neurology Authors: Sona C, Kumar A, Dogra S, Kumar BA, Umrao D, Yadav PN Tags: Neurobiol Dis Source Type: research

Neuroimaging markers of antipsychotic treatment response in schizophrenia: An overview of magnetic resonance imaging studies.
Abstract Antipsychotic drugs are the primary treatment for psychosis, yet individual response to their administration remains variable. At present, no biological predictors of response exist to guide clinicians as they select treatments for patients, and our understanding of the neurobiology underlying the heterogeneity of outcomes remains limited. Magnetic Resonance Imaging (MRI) has been applied by numerous studies to examine the response to antipsychotic treatment, though a large gap remains between their results and our clinical practice. To advance patient care with precision medicine approaches, prior work m...
Source: Neurobiology of Disease - June 25, 2018 Category: Neurology Authors: Tarcijonas G, Sarpal DK Tags: Neurobiol Dis Source Type: research

CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways.
Abstract White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation o...
Source: Neurobiology of Disease - June 23, 2018 Category: Neurology Authors: Bastian C, Quinn J, Tripathi A, Aquila D, Dutta AMR, Baltan S, Brunet S Tags: Neurobiol Dis Source Type: research

α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy.
In conclusion, we have revealed a novel neuroprotective activity of MPS that is>100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases. PMID: 29940336 [PubMed - as suppli...
Source: Neurobiology of Disease - June 22, 2018 Category: Neurology Authors: Wong SQ, Pontifex MG, Phelan MM, Pidathala C, Kraemer BC, Barclay JW, Berry NG, O'Neill PM, Burgoyne RD, Morgan A Tags: Neurobiol Dis Source Type: research

Glycogen synthase kinase-3 β inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A.
Glycogen synthase kinase-3β inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A. Neurobiol Dis. 2018 Jun 22;: Authors: Dohare P, Cheng B, Ahmed E, Yadala V, Singla P, Thomas S, Kayton R, Ungvari Z, Ballabh P Abstract Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized th...
Source: Neurobiology of Disease - June 22, 2018 Category: Neurology Authors: Dohare P, Cheng B, Ahmed E, Yadala V, Singla P, Thomas S, Kayton R, Ungvari Z, Ballabh P Tags: Neurobiol Dis Source Type: research

Alterations in cortical interneurons and cognitive function in schizophrenia.
Abstract Certain clinical features of schizophrenia, such as working memory disturbances, appear to emerge from altered gamma oscillatory activity in the prefrontal cortex (PFC). Given the essential role of GABA neurotransmission in both working memory and gamma oscillations, understanding the cellular substrate for their disturbances in schizophrenia requires evidence from in vivo neuroimaging studies, which provide a means to link markers of GABA neurotransmission to gamma oscillations and working memory, and from postmortem studies, which provide insight into GABA neurotransmission at molecular and cellular lev...
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Dienel SJ, Lewis DA Tags: Neurobiol Dis Source Type: research

In search of antiepileptogenic treatments for post-traumatic epilepsy.
ou AS Abstract Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the ex...
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Saletti PG, Ali I, Casillas-Espinosa PM, Semple BD, Lisgaras C, Moshé SL, Galanopoulou AS Tags: Neurobiol Dis Source Type: research

V363I and V363A mutated tau affect aggregation and neuronal dysfunction differently in C. elegans.
Abstract Mutations in the microtubule-associated protein tau (MAPT) gene have been linked to a heterogeneous group of progressive neurodegenerative disorders commonly called tauopathies. From patients with frontotemporal lobar degeneration with distinct atypical clinical phenotypes, we recently identified two new mutations on the same codon, in position 363 of the MAPT gene, which resulted in the production of Val-to-Ala (tauV363A) or Val-to-Ile (tauV363I) mutated tau. These substitutions specifically affected microtubule polymerization and propensity of tau to aggregate in vitro suggesting that single amino acid ...
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Morelli F, Romeo M, Barzago MM, Bolis M, Mattioni D, Rossi G, Tagliavini F, Bastone A, Salmona M, Diomede L Tags: Neurobiol Dis Source Type: research

The neurobiological effects of repetitive head impacts in collision sports.
Abstract It is now recognized that repetitive head impacts (RHI) in sport have the potential for long-term neurological impairments. In order to identify targets for intervention and/or pharmacological treatment it is necessary to characterize the neurobiological mechanisms associated with RHI. This review aims to summarize animal and human studies that specifically address Blood Brain Barrier (BBB) dysfunction, abnormal neuro-metabolic and neuro-inflammatory processes as well as Tau aggregation associated with RHI in collision sports. Additionally, we examine the influence of physical activity and genetics on out...
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Hunter LE, Branch CA, Lipton ML Tags: Neurobiol Dis Source Type: research

The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing/degrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia.
The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last l...
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Rojo-Bustamante E, Abellanas MA, Clavero P, Thiolat ML, Li Q, Luquin MR, Bezard E, Aymerich MS Tags: Neurobiol Dis Source Type: research

A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability.
PMID: 29936235 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - June 21, 2018 Category: Neurology Authors: Bonzanni M, DiFrancesco JC, Milanesi R, Campostrini G, Castellotti B, Bucchi A, Baruscotti M, Ferrarese C, Franceschetti S, Canafoglia L, Ragona F, Freri E, Labate A, Gambardella A, Costa C, Rivolta I, Gellera C, Granata T, Barbuti A, DiFrancesco D Tags: Neurobiol Dis Source Type: research

Imaging correlates of behavioral impairments: An experimental PET study in the rat pilocarpine epilepsy model.
In conclusion, μPET data from rats with pilocarpine-induced epileptogenesis indicate altered septal 5-HT1A receptor binding. Further research is necessary assessing whether septal 5-HT1A receptor binding may serve as an imaging correlate of neuropsychiatric comorbidities in epilepsy patients and for severity assessment in rodent epilepsy models. In contrast, we obtained evidence that [18F]FDG uptake also reflects the severity of epilepsy and, thus, might not constitute a biomarker with sufficient specificity for psychiatric comorbidities. Evidence has been obtained that BDNF might serve as a peripheral circulatory bioma...
Source: Neurobiology of Disease - June 19, 2018 Category: Neurology Authors: Di Liberto V, Maarten van Dijk R, Brendel M, Waldron AM, Möller C, Koska I, Seiffert I, Gualtieri F, Gildehaus FJ, von Ungern-Sternberg B, Lindner M, Ziegler S, Palme R, Hellweg R, Gass P, Bartenstein P, Potschka H Tags: Neurobiol Dis Source Type: research

What is the therapeutic mechanism of pedunculopontine nucleus stimulation in Parkinson's disease?
Abstract Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is an experimental treatment for in Parkinson's disease (PD) which offers a fairly circumscribed benefit for gait freezing and perhaps balance impairment. The benefit on gait freezing is variable and typically incomplete, which may reflect that the clinical application is yet to be optimised or reflect a fundamental limitation of the therapeutic mechanism. Thus, a better understanding of the therapeutic mechanism of PPN DBS may guide the further development of this therapy. The available evidence supports that the PPN is underactive in PD due to ...
Source: Neurobiology of Disease - June 19, 2018 Category: Neurology Authors: Thevathasan W, Moro E Tags: Neurobiol Dis Source Type: research

Beta burst coupling across the motor circuit in Parkinson's disease.
own P Abstract Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Her...
Source: Neurobiology of Disease - June 14, 2018 Category: Neurology Authors: Tinkhauser G, Torrecillos F, Duclos Y, Tan H, Pogosyan A, Fischer P, Carron R, Welter ML, Karachi C, Vandenberghe W, Nuttin B, Witjas T, Régis J, Azulay JP, Eusebio A, Brown P Tags: Neurobiol Dis Source Type: research

Dopamine D2 receptor activation potently inhibits striatal glutamatergic transmission in a G2019S LRRK2 genetic model of Parkinson's disease.
Abstract Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk...
Source: Neurobiology of Disease - June 13, 2018 Category: Neurology Authors: Tozzi A, Durante V, Bastioli G, Mazzocchetti P, Novello S, Mechelli A, Morari M, Costa C, Mancini A, Di Filippo M, Calabresi P Tags: Neurobiol Dis Source Type: research

Protein coding mitochondrial-targeted RNAs rescue mitochondrial disease in vivo.
Abstract Mitochondrial encephalomyopathies (MEs) result from mutations in mitochondrial genes critical to oxidative phosphorylation. Severe and untreatable ME results from mutations affecting each endogenous mitochondrial encoded gene, including all 13 established protein coding genes. Effective techniques to manipulate mitochondrial genome are limited and targeted mitochondrial protein expression is currently unavailable. Here we report the development of a mitochondrial-targeted RNA expression (mtTRES) vector capable of protein expression within mitochondria (mtTRESPro). We demonstrate that mtTRESPro expressed R...
Source: Neurobiology of Disease - June 13, 2018 Category: Neurology Authors: Markantone DM, Towheed A, Crain AT, Collins JM, Celotto AM, Palladino MJ Tags: Neurobiol Dis Source Type: research

Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study.
s DJ Abstract OBJECTIVE: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-β and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). METHODS: Six clinically probable AD and 20 MCI subjects had inflammation (11C-(R)-PK11195), amyloid (11C-PiB) and tau (18F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses...
Source: Neurobiology of Disease - June 11, 2018 Category: Neurology Authors: Parbo P, Ismail R, Sommerauer M, Stokholm MG, Hansen AK, Hansen KV, Amidi A, Schaldemose JL, Gottrup H, Brændgaard H, Eskildsen SF, Borghammer P, Hinz R, Aanerud J, Brooks DJ Tags: Neurobiol Dis Source Type: research