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

Glutamatergic nervous system degeneration in a C. elegans. TauA152T tauopathy model involves pathways of excitotoxicity and Ca2+ dysregulation.
PMID: 29894752 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - June 9, 2018 Category: Neurology Authors: Choudhary B, Mandelkow E, Mandelkow EM, Pir GJ Tags: Neurobiol Dis Source Type: research

Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy.
Abstract Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy, however there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extend t...
Source: Neurobiology of Disease - June 9, 2018 Category: Neurology Authors: Wang Y, Liang J, Chen L, Shen Y, Zhao J, Xu C, Wu X, Cheng H, Ying X, Guo Y, Wang S, Zhou Y, Wang Y, Chen Z Tags: Neurobiol Dis Source Type: research

Bexarotene protects against neurotoxicity partially through a PPAR γ-dependent mechanism in mice following traumatic brain injury.
Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury. Neurobiol Dis. 2018 Jun 07;: Authors: He J, Liu H, Zhong J, Guo Z, Wu J, Zhang H, Huang Z, Jiang L, Li H, Zhang Z, Liu L, Wu Y, Qi L, Sun X, Cheng C Abstract Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated t...
Source: Neurobiology of Disease - June 7, 2018 Category: Neurology Authors: He J, Liu H, Zhong J, Guo Z, Wu J, Zhang H, Huang Z, Jiang L, Li H, Zhang Z, Liu L, Wu Y, Qi L, Sun X, Cheng C Tags: Neurobiol Dis Source Type: research

Electrophysiological biomarkers of epileptogenicity after traumatic brain injury.
Abstract Post-traumatic epilepsy is the architype of acquired epilepsies, wherein a brain insult initiates an epileptogenic process culminating in an unprovoked seizure after weeks, months or years. Identifying biomarkers of such process is a prerequisite for developing and implementing targeted therapies aimed at preventing the development of epilepsy. Currently, there are no validated electrophysiological biomarkers of post-traumatic epileptogenesis. Experimental EEG studies using the lateral fluid percussion injury model have identified three candidate biomarkers of post-traumatic epileptogenesis: pathological ...
Source: Neurobiology of Disease - June 5, 2018 Category: Neurology Authors: Perucca P, Smith G, Santana-Gomez C, Bragin A, Staba R Tags: Neurobiol Dis Source Type: research

Minocycline attenuates brain injury and iron overload after intracerebral hemorrhage in aged female rats.
Abstract Brain iron overload is involved in brain injury after intracerebral hemorrhage (ICH). There is evidence that systemic administration of minocycline reduces brain iron level and improves neurological outcome in experimental models of hemorrhagic and ischemic stroke. However, there is evidence in cerebral ischemia that minocycline is not protective in aged female animals. Since most ICH research has used male models, this study was designed to provide an overall view of ICH-induced iron deposits at different time points (1 to 28 days) in aged (18-month old) female Fischer 344 rat ICH model and to investig...
Source: Neurobiology of Disease - June 4, 2018 Category: Neurology Authors: Dai S, Hua Y, Keep RF, Novakovic N, Fei Z, Xi G Tags: Neurobiol Dis Source Type: research

Big data sharing and analysis to advance research in post-traumatic epilepsy.
We describe the infrastructure and functionality for a centralized preclinical and clinical data repository and analytic platform to support importing heterogeneous multi-modal data, automatically and manually linking data across modalities and sites, and searching content. We have developed and applied innovative image and electrophysiology processing methods to identify candidate biomarkers from MRI, EEG, and multi-modal data. Based on heterogeneous biomarkers, we present novel analytic tools designed to study epileptogenesis in animal model and human with the goal of tracking the probability of developing epilepsy over ...
Source: Neurobiology of Disease - June 1, 2018 Category: Neurology Authors: Duncan D, Vespa P, Pitkanen A, Braimah A, Lapinlampi N, Toga AW Tags: Neurobiol Dis Source Type: research

Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center.
This study indicates that data-driven subgroups of MCI are clinicopathologically informative and, with refinement, could lead to targeted interventions focused on each etiology. PMID: 29859866 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Hanfelt JJ, Peng L, Goldstein FC, Lah JJ Tags: Neurobiol Dis Source Type: research

Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease.
Agostinho P Abstract Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A2A receptors (A2AR) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A2A receptors (A2AR) causes memory deficits and the blockade of A2AR prevents memory damage in AD models. We now enquired if this prophylactic role of A2AR might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations. At the onset ...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Silva AC, Lemos C, Gonçalves FQ, Pliássova AV, Machado NJ, Silva HB, Canas PM, Cunha RA, Lopes JP, Agostinho P Tags: Neurobiol Dis Source Type: research

Organophosphate pesticide chlorpyrifos impairs STAT1 signaling to induce dopaminergic neurotoxicity: Implications for mitochondria mediated oxidative stress signaling events.
Abstract The organophosphate (OP) pesticide chlorpyrifos (CPF), used in agricultural settings, induces developmental and neurological impairments. Recent studies using in vitro cell culture models have reported CPF exposure to have a positive association with mitochondria-mediated oxidative stress response and dopaminergic cell death; however, the mechanism by which mitochondrial reactive oxygen species (ROS) contribute to dopaminergic cell death remains unclear. Therefore, we hypothesized that STAT1, a transcription factor, causes apoptotic dopaminergic cell death via mitochondria-mediated oxidative stress mechan...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Singh N, Lawana V, Luo J, Phong P, Abdalla A, Palanisamy B, Rokad D, Sarkar S, Jin H, Anantharam V, Kanthasamy AG, Kanthasamy A Tags: Neurobiol Dis Source Type: research

Neuronal levels and sequence of tau modulate the power of brain rhythms.
Abstract Neural network dysfunction may contribute to functional decline and disease progression in neurodegenerative disorders. Diverse lines of evidence suggest that neuronal accumulation of tau promotes network dysfunction and cognitive decline. The A152T-variant of human tau (hTau-A152T) increases the risk of Alzheimer's disease (AD) and several other tauopathies. When overexpressed in neurons of transgenic mice, it causes age-dependent neuronal loss and cognitive decline, as well as non-convulsive epileptic activity, which is also seen in patients with AD. Using intracranial EEG recordings with electrodes imp...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Das M, Maeda S, Hu B, Yu GQ, Guo W, Lopez I, Yu X, Tai C, Wang X, Mucke L Tags: Neurobiol Dis Source Type: research

Multiple sclerosis and mixed microbial infections. Direct identification of fungi and bacteria in nervous tissue.
In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury. PMID: 29859870 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Alonso R, Fernández-Fernández AM, Pisa D, Carrasco L Tags: Neurobiol Dis Source Type: research

Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease.
Abstract Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating ...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Tiernan CT, Ginsberg SD, He B, Ward SM, Guillozet-Bongaarts AL, Kanaan NM, Mufson EJ, Counts SE Tags: Neurobiol Dis Source Type: research

Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study.
, 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, Naughton T, 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 L Abstract OBJECTIVE: Injury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (PTE). However, whether lesion lo...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Tubi MA, Lutkenhoff E, Blanco MB, McArthur D, Villablanca P, Ellingson B, Diaz-Arrastia R, Van Ness P, Real C, Shrestha V, Engel J, Vespa PM, EpiBioS4Rx Study Group Investigators, Agoston D, Au A, Bell MJ, Branch C, Buitrago Blanco M, Bullock R, Claassen Tags: Neurobiol Dis Source Type: research

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.
Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein. Neurobiol Dis. 2018 May 31;: Authors: Subramaniam SR, Magen I, Bove N, Zhu C, Lemesre V, Dutta G, Elias CJ, Lester HA, Chesselet MF Abstract In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-sy...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Subramaniam SR, Magen I, Bove N, Zhu C, Lemesre V, Dutta G, Elias CJ, Lester HA, Chesselet MF Tags: Neurobiol Dis Source Type: research

Newfound effect of N-acetylaspartate in preventing and reversing aggregation of amyloid-beta in vitro.
th DH Abstract Although N-acetylaspartate (NAA) has long been recognized as the most abundant amino acid in neurons by far, its primary role has remained a mystery. Based on its unique tertiary structure, we explored the potential of NAA to modulate aggregation of amyloid-beta (Aβ) peptide 1-42 via multiple corroborating aggregation assays along with electron microscopy. Thioflavin-T fluorescence assay demonstrated that at physiological concentrations, NAA substantially inhibited the initiation of Aβ fibril formation. In addition, NAA added after 25 min of Aβ aggregation was shown to break up pref...
Source: Neurobiology of Disease - May 31, 2018 Category: Neurology Authors: Dollé JP, Rodgers JM, Browne KD, Troxler T, Gai F, Smith DH Tags: Neurobiol Dis Source Type: research

Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.
Abstract The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow ...
Source: Neurobiology of Disease - May 30, 2018 Category: Neurology Authors: Xu X, Yin D, Ren H, Gao W, Li F, Sun D, Wu Y, Zhou S, Lyu L, Yang M, Xiong J, Han L, Jiang R, Zhang J Tags: Neurobiol Dis Source Type: research

Lysosome trafficking and signaling in health and neurodegenerative diseases.
Abstract Lysosomes, single-membrane organelles defined by a uniquely acidic lumenal pH and high content of acid hydrolases, are the shared degradative compartments of the endocytic and autophagic pathways. These pathways, and especially lysosomes, are points of particular vulnerability in many neurodegenerative diseases. Beyond the role of lysosomes in substrate degradation, new findings have ascribed lysosomes with the leading role in sensing and responding to cellular nutrients, growth factors and cellular stress. This review aims to integrate recent concepts of basic lysosome biology and pathobiology as a basis...
Source: Neurobiology of Disease - May 30, 2018 Category: Neurology Authors: Lie PPY, Nixon RA Tags: Neurobiol Dis Source Type: research

Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF production.
Abstract The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediatin...
Source: Neurobiology of Disease - May 30, 2018 Category: Neurology Authors: Cotto B, Li H, Tuma RF, Ward SJ, Langford D Tags: Neurobiol Dis Source Type: research

Correlation between cortical beta power and gait speed is suppressed in a parkinsonian model, but restored by therapeutic deep brain stimulation.
Abstract The motor cortex and subthalamic nucleus (STN) of patients with Parkinson's disease (PD) exhibit abnormally high levels of electrophysiological oscillations in the ~12-35 Hz beta-frequency range. Recent studies have shown that beta is partly carried forward to regulate future motor states in the healthy condition, suggesting that steady state beta power is lower when a sequence of movements occurs in a short period of time, such as during fast gait. However, whether this relationship between beta power and motor states persists upon parkinsonian onset or in response to effective therapy is unclear. Usin...
Source: Neurobiology of Disease - May 30, 2018 Category: Neurology Authors: Polar CA, Gupta R, Lehmkuhle MJ, Dorval AD Tags: Neurobiol Dis Source Type: research

TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities.
Abstract Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB)...
Source: Neurobiology of Disease - May 28, 2018 Category: Neurology Authors: Cortes CJ, La Spada AR Tags: Neurobiol Dis Source Type: research

Chaperone-mediated autophagy: Advances from bench to bedside.
Abstract Protein homeostasis or proteostasis is critical for proper cellular function and survival. It relies on the balance between protein synthesis and degradation. Lysosomes play an important role in degrading and recycling intracellular components via autophagy. Among the three types of lysosome-based autophagy pathways, chaperone-mediated autophagy (CMA) selectively degrades cellular proteins with KFERQ-like motif by unique machinery. During the past several years, significant advances have been made in our understanding of how CMA itself is modulated and what physiological and pathological processes it may ...
Source: Neurobiology of Disease - May 22, 2018 Category: Neurology Authors: Li W, Nie T, Xu H, Yang J, Yang Q, Mao Z Tags: Neurobiol Dis Source Type: research

Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress.
Abstract Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD, as well as 5-10% of sporadic ALS. Despite the location of the HRE in the non-coding region (with respect to the main C9ORF72 gene product), dipeptide repeat proteins (DPRs) that are thought to be toxic are translated from the HRE in all three reading frames from both the sense and antisense transcript. Here, we identified a CUG translation initiation codon that has a good Kozak consensus sequence as the t...
Source: Neurobiology of Disease - May 21, 2018 Category: Neurology Authors: Sonobe Y, Ghadge G, Masaki K, Sendoel A, Fuchs E, Roos RP Tags: Neurobiol Dis Source Type: research

Epilepsy biomarkers - Toward etiology and pathology specificity.
a N PMID: 29782966 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - May 18, 2018 Category: Neurology Authors: Pitkänen A, Ndode-Ekane X, Lapinlampi N, Puhakka N Tags: Neurobiol Dis Source Type: research

Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease.
Abstract The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD. Here, we evaluated the functionin...
Source: Neurobiology of Disease - May 17, 2018 Category: Neurology Authors: Cordella A, Krashia P, Nobili A, Pignataro A, La Barbera L, Viscomi MT, Valzania A, Keller F, Ammassari-Teule M, Mercuri NB, Berretta N, D'Amelio M Tags: Neurobiol Dis Source Type: research

Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro.
In this study, we show that exogenous application of these deoxysphingoid bases causes dose- and time-dependent neurotoxicity in primary mammalian neurons, as determined by analysis of cell survival and neurite length. Acutely, deoxysphingoid base neurotoxicity manifests in abnormal Ca2+ handling by the endoplasmic reticulum (ER) and mitochondria as well as dysregulation of cell membrane store-operated Ca2+ channels. The changes in intracellular Ca2+ handling are accompanied by an early loss of mitochondrial membrane potential in deoxysphingoid base-treated motor and sensory neurons. Thus, these results suggest that exogen...
Source: Neurobiology of Disease - May 17, 2018 Category: Neurology Authors: Wilson ER, Kugathasan U, Abramov AY, Clark AJ, Bennett DLH, Reilly MM, Greensmith L, Kalmar B Tags: Neurobiol Dis Source Type: research

PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy.
In this study we show that PCDH19 is highly expressed in human neural stem and progenitor cells (NSPCs) and investigate its function in vitro in these cells of both mouse and human origin. Transcriptomic analysis of mouse NSPCs lacking Pcdh19 revealed changes to genes involved in regulation of neuronal differentiation, and we subsequently show that loss of Pcdh19 causes increased NSPC neurogenesis. We reprogramed human fibroblast cells harbouring a pathogenic PCDH19 mutation into human induced pluripotent stem cells (hiPSC) and employed neural differentiation of these to extend our studies into human NSPCs. As in mouse, lo...
Source: Neurobiology of Disease - May 12, 2018 Category: Neurology Authors: Homan CC, Pederson S, To TH, Tan C, Piltz S, Corbett M, Wolvetang E, Thomas P, Jolly LA, Gecz J Tags: Neurobiol Dis Source Type: research

Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model.
war S Abstract Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediate...
Source: Neurobiology of Disease - May 11, 2018 Category: Neurology Authors: Pérez Ortiz JM, Mollema N, Toker N, Adamski CJ, O'Callaghan B, Duvick L, Friedrich J, Walters MA, Strasser J, Hawkinson JE, Zoghbi HY, Henzler C, Orr HT, Lagalwar S Tags: Neurobiol Dis Source Type: research

A mechanistic review on GNAO1-associated movement disorder.
Abstract Mutations in the GNAO1 gene cause a complex constellation of neurological disorders including epilepsy, developmental delay, and movement disorders. GNAO1 encodes Gαo, the α subunit of Go, a member of the Gi/o family of heterotrimeric G protein signal transducers. Go is the most abundant membrane protein in the mammalian central nervous system and plays major roles in synaptic neurotransmission and neurodevelopment. GNAO1 mutations were first reported in early infantile epileptic encephalopathy 17 (EIEE17) but are also associated with a more common syndrome termed neurodevelopmental disorder w...
Source: Neurobiology of Disease - May 11, 2018 Category: Neurology Authors: Feng H, Khalil S, Neubig RR, Sidiropoulos C Tags: Neurobiol Dis Source Type: research

Polarization-sensitive optical coherence tomography reveals gray matter and white matter atrophy in SCA1 mouse models.
In this study, we demonstrate the label-free optical imaging methodology that can detect, with a high degree of sensitivity, discrete areas of degeneration in the cerebellum of the SCA1 mouse models. We used ATXN1[82Q] and ATXN1[30Q]-D776 mice in which the transgene is directed only to Purkinje cells. Molecular layer, granular layer, and white matter regions are analyzed using the intrinsic contrasts provided by polarization-sensitive optical coherence tomography. Cerebellar atrophy in SCA1 mice occurred both in gray matter and white matter. While gray matter atrophy is obvious, indications of white matter atrophy includin...
Source: Neurobiology of Disease - May 10, 2018 Category: Neurology Authors: Liu CJ, Rainwater O, Brent Clark H, Orr HT, Akkin T Tags: Neurobiol Dis Source Type: research

Regulation of seizure-induced MeCP2 Ser421 phosphorylation in the developing brain.
Abstract Neonatal seizures disrupt normal synaptic maturation and often lead to later-life epilepsy and cognitive deficits. During early life, the brain exhibits heightened synaptic plasticity, in part due to a developmental overabundance of CaV1.2 L-type voltage gated calcium (Ca2+) channels (LT-VGCCs) and Ca2+-permeable AMPARs (CP-AMPARs) lacking GluA2 subunits. We hypothesized that early-life seizures overactivate these channels, in turn dysregulating Ca2+-dependent signaling pathways including that of methyl-CPG-binding protein 2 (MeCP2), a transcription factor implicated in the autism spectrum disorder (ASD) ...
Source: Neurobiology of Disease - May 5, 2018 Category: Neurology Authors: Rosenberg EC, Lippman-Bell JJ, Handy M, Soldan SS, Rakhade S, Hilario-Gomez C, Folweiler K, Jacobs L, Jensen FE Tags: Neurobiol Dis Source Type: research

Contribution of induced pluripotent stem cell technologies to the understanding of cellular phenotypes in schizophrenia.
Abstract Schizophrenia is one of the leading causes of disability among mental disorders, contributing to a substantial socioeconomic burden. Our understanding of the mechanisms of the pathogenesis of the disease has largely been limited by its inherent complexity imparted by the polygenicity and interactions with environmental factors. Since pathobiological events are initiated in the schizophrenic brain long before the onset of the psychotic manifestations, characterizing these processes is limited, mainly due to a lack of access to neuronal tissues. Induced pluripotent stem cell (iPSC) technologies have provide...
Source: Neurobiology of Disease - May 2, 2018 Category: Neurology Authors: Balan S, Toyoshima M, Yoshikawa T Tags: Neurobiol Dis Source Type: research

High frequency stimulation of the anterior vermis modulates behavioural response to chronic stress: Involvement of the prefrontal cortex and dorsal raphe?
Abstract Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress ...
Source: Neurobiology of Disease - May 1, 2018 Category: Neurology Authors: Bambico FR, Comai S, Hasan MSN, Conway JD, Darvish-Gane S, Hamani C, Gobbi G, Nobrega JN Tags: Neurobiol Dis Source Type: research

Crosstalk between presynaptic trafficking and autophagy in Parkinson's disease.
Abstract Parkinson's disease (PD) is a debilitating neurodegenerative disorder that profoundly affects one's motor functions. The disease is characterized pathologically by denervation of dopaminergic (DAergic) nigrostriatal terminal and degeneration of DAergic neurons in the substantia nigra par compacta (SNpc); however, the precise molecular mechanism underlying disease pathogenesis remains poorly understood. Animal studies in both toxin-induced and genetic PD models suggest that presynaptic impairments may underlie the early stage of DA depletion and neurodegeneration (reviewed in Schirinzi, T., et al. 2016). S...
Source: Neurobiology of Disease - April 30, 2018 Category: Neurology Authors: Pan PY, Zhu Y, Shen Y, Yue Z Tags: Neurobiol Dis Source Type: research

Salidroside mediated stabilization of Bcl -xL prevents mitophagy in CA3 hippocampal neurons during hypoxia.
Abstract Chronic hypoxic stress results in deposition of lipofuscin granules in the CA3 region of hippocampal neurons which contributes to neurodegeneration and accelerated neuronal aging. Oxidative stress and mitophagy during hypoxia are crucial to cause aggregation of these lipofuscin granules in hypoxic neurons. Salidroside, a glucoside derivative of β-Tyrosol, has been reported to protect hypoxic neurons through maintenance of mitochondrial activity. The present study is aimed at investigating the potential of Salidroside in preventing mitophagy during chronic hypoxia and identification of the molecular t...
Source: Neurobiology of Disease - April 30, 2018 Category: Neurology Authors: Biswal S, Barhwal KK, Das D, Dhingra R, Dhingra N, Nag TC, Hota SK Tags: Neurobiol Dis Source Type: research

Roles for neuronal and microglial autophagy in synaptic pruning during development.
Abstract The dendritic protrusions known as spines represent the primary postsynaptic location for excitatory synapses. Dendritic spines are critical for synaptic function, and their formation, modification, and turnover are thought to be important for mechanisms of learning and memory. At many synapses, dendritic spines form during the early postnatal period, and while many spines are likely being formed and removed throughout life, the net number are often gradually "pruned" during adolescence to reach a stable level in the adult. In neurodevelopmental disorders, spine pruning is disrupted, emphasizing...
Source: Neurobiology of Disease - April 27, 2018 Category: Neurology Authors: Lieberman OJ, McGuirt AF, Tang G, Sulzer D Tags: Neurobiol Dis Source Type: research

Plasma α-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study.
Plasma α-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study. Neurobiol Dis. 2018 Apr 26;: Authors: Wang H, Atik A, Stewart T, Ginghina C, Aro P, Kerr KF, Seibyl J, Jennings D, PARS Investigators, Jensen PH, Marek K, Shi M, Zhang J Abstract Plasma total and nervous system derived exosomal (NDE) α-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma α-synuclein in the prodromal phase of PD, plasma total and NDE α-synuclein were evaluated in baseline and 2-year follow-up samp...
Source: Neurobiology of Disease - April 26, 2018 Category: Neurology Authors: Wang H, Atik A, Stewart T, Ginghina C, Aro P, Kerr KF, Seibyl J, Jennings D, PARS Investigators, Jensen PH, Marek K, Shi M, Zhang J Tags: Neurobiol Dis Source Type: research

Fibronectin EDA forms the chronic fibrotic scar after contusive spinal cord injury.
In this study, we examined the effects of eliminating an isoform of fibronectin containing the Extra Domain A domain (FnEDA) on both fibrosis and on functional recovery after contusion SCI using male and female FnEDA-null mice. Eliminating FnEDA did not reduce the acute fibrotic response but markedly diminished chronic fibrotic scarring after SCI. Glial scarring was unchanged after SCI in FnEDA-null mice. We found that FnEDA was important for the long-term stability of the assembled fibronectin matrix during both the subacute and chronic phases of SCI. Motor functional recovery was significantly improved, and there were in...
Source: Neurobiology of Disease - April 26, 2018 Category: Neurology Authors: Cooper JG, Jeong SJ, McGuire TL, Sharma S, Wang W, Bhattacharyya S, Varga J, Kessler JA Tags: Neurobiol Dis Source Type: research

Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis.
We reported recently that chronic partial inhibition of brain glycolysis triggers epileptogenesis in healthy rats. Here, by monitoring dynamic electrical and multiple metabolic parameters before and following seizure generation in mouse hippocampal slices using the 4-aminopyridine model of epileptiform activity, we show that in turn seizures are followed by a long-lasting glucose hypometabolism, indicating possible existence of a positive feedback in the mechanism of epileptogenesis. Seizures were associated with acute oxidative stress that may contribute to the subsequent glucose metabolism impairment, since exogenous app...
Source: Neurobiology of Disease - April 26, 2018 Category: Neurology Authors: Malkov A, Ivanov AI, Buldakova S, Waseem T, Popova I, Zilberter M, Zilberter Y Tags: Neurobiol Dis Source Type: research

Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster.
We examined the importance of this interaction in ataxin-3-dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP-binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA-interference has a similar, protective effect to mutating the VCP-binding site of pathogenic ataxin...
Source: Neurobiology of Disease - April 25, 2018 Category: Neurology Authors: Ristic G, Sutton JR, Libohova K, Todi SV Tags: Neurobiol Dis Source Type: research

The role of autophagy in acute brain injury: A state of flux?
Abstract It is established that increased autophagy is readily detectable after various types of acute brain injury, including trauma, focal and global cerebral ischemia. What remains controversial, however, is whether this heightened detection of autophagy in brain represents a homeostatic or pathologic process, or an epiphenomenon. The ultimate role of autophagy after acute brain injury likely depends upon: (Galluzzi et al., 2016) the degree of brain injury and the overall autophagic burden; (Smith et al., 2011) the capacity of individual cell types to ramp up autophagic flux; (Mizushima et al., 2004) the local ...
Source: Neurobiology of Disease - April 25, 2018 Category: Neurology Authors: Wolf MS, Bayır H, Kochanek PM, Clark RSB Tags: Neurobiol Dis Source Type: research

Sleep dysfunction following neonatal ischemic seizures are differential by neonatal age of insult as determined by qEEG in a mouse model.
Abstract Neonatal seizures associated with hypoxic-ischemic encephalopathy (HIE) pose a challenge in their acute clinical management and are often followed by long-term neurological consequences. We used a newly characterized CD-1 mouse model of neonatal ischemic seizures associated with age-dependent (P7 vs. P10) seizure severity and phenobarbital efficacy (i.e.; PB-resistant vs. PB-efficacious respectively) following unilateral carotid ligation. The long-term consequences following untreated neonatal seizures in P7 vs. P10 ligated pups were investigated using neurobehavioral testing, 24 h v- quantitative EEG -...
Source: Neurobiology of Disease - April 20, 2018 Category: Neurology Authors: Kang SK, Ammanuel S, Thodupunuri S, Adler DA, Johnston MV, Kadam SD Tags: Neurobiol Dis Source Type: research

Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV- α-synuclein is normalized by LRRK2 modulation.
Parkinson's disease-like burst firing activity in subthalamic nucleus induced by AAV-α-synuclein is normalized by LRRK2 modulation. Neurobiol Dis. 2018 Apr 19;: Authors: Andersen MA, Christensen KV, Badolo L, Smith GP, Jeggo R, Jensen PH, Andersen KJ, Sotty F Abstract Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, le...
Source: Neurobiology of Disease - April 19, 2018 Category: Neurology Authors: Andersen MA, Christensen KV, Badolo L, Smith GP, Jeggo R, Jensen PH, Andersen KJ, Sotty F Tags: Neurobiol Dis Source Type: research

Modulating membrane fluidity corrects Batten disease phenotypes in vitro and in vivo.
Abstract The neuronal ceroid lipofuscinoses are a class of inherited neurodegenerative diseases characterized by the accumulation of autofluorescent storage material. The most common neuronal ceroid lipofuscinosis has juvenile onset with rapid onset blindness and progressive degeneration of cognitive processes. The juvenile form is caused by mutations in the CLN3 gene, which encodes the protein CLN3. While mouse models of Cln3 deficiency show mild disease phenotypes, it is apparent from patient tissue- and cell-based studies that its loss impacts many cellular processes. Using Cln3 deficient mice, we previously de...
Source: Neurobiology of Disease - April 13, 2018 Category: Neurology Authors: Schultz ML, Tecedor L, Lysenko E, Ramachandran S, Stein CS, Davidson BL Tags: Neurobiol Dis Source Type: research

A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia.
oli E Abstract The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca2+ signaling in neurons demands the continuous activity of Ca2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca2+ATPases (PMCA pumps) play a key role in the regulation of Ca2+ handling in selected ...
Source: Neurobiology of Disease - April 12, 2018 Category: Neurology Authors: Vicario M, Zanni G, Vallese F, Santorelli F, Grinzato A, Cieri D, Berto P, Frizzarin M, Lopreiato R, Zonta F, Ferro S, Sandre M, Marin O, Ruzzene M, Bertini E, Zanotti G, Brini M, Calì T, Carafoli E Tags: Neurobiol Dis Source Type: research

Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling.
Abstract Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. In the present study, we tested the hypothesis that the novel antidepressant agomelatine, a potent melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist, can prevent depressive symptoms developed during the chronic epileptic phase by suppressing an inflammatory response. Chronic treatment with agomelatine (40 mg/kg, i.p.) was initiated an hour after the kainate acid (KA)-induced status epilepticus (SE) and maintained for a period of 10 weeks in Wistar rats. R...
Source: Neurobiology of Disease - April 10, 2018 Category: Neurology Authors: Tchekalarova J, Atanasova D, Kortenska L, Atanasova M, Lazarov N Tags: Neurobiol Dis Source Type: research

Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson's disease.
Abstract DJ-1 is a redox-sensitive protein with several putative functions important in mitochondrial physiology, protein transcription, proteasome regulation, and chaperone activity. High levels of DJ-1 immunoreactivity are reported in astrocytes surrounding pathology associated with idiopathic Parkinson's disease, possibly reflecting the glial response to oxidative damage. Previous studies showed that astrocytic over-expression of DJ-1 in vitro prevented oxidative stress and mitochondrial dysfunction in primary neurons. Based on these observations, we developed a pseudotyped lentiviral gene transfer vector with ...
Source: Neurobiology of Disease - April 9, 2018 Category: Neurology Authors: De Miranda BR, Rocha EM, Bai Q, El Ayadi A, Hinkle D, Burton EA, Timothy Greenamyre J Tags: Neurobiol Dis Source Type: research

Dynamic interneuron-principal cell interplay leads to a specific pattern of in vitro ictogenesis.
oli M Abstract Ictal discharges induced by 4-aminopyridine in the in vitro rodent entorhinal cortex present with either low-voltage fast or sudden onset patterns. The role of interneurons in initiating low-voltage fast onset ictal discharges is well established but the processes leading to sudden onset ictal discharges remain unclear. We analysed here the participation of interneurons (n = 75) and principal cells (n = 13) in the sudden onset pattern by employing in vitro tetrode wire recordings in the entorhinal cortex of brain slices from Sprague-Dawley rats. Ictal discharges emerged from a background of ...
Source: Neurobiology of Disease - April 7, 2018 Category: Neurology Authors: Lévesque M, Chen LY, Hamidi S, Avoli M Tags: Neurobiol Dis Source Type: research