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Neurobiology of Disease

Asla Pitkänen, Xavier Ndode-Ekane, Niina Lapinlampi, Noora Puhakka
No abstract text is available yet for this article.
May 18, 2018: Neurobiology of Disease
Emma R Wilson, Umaiyal Kugathasan, Andrey Y Abramov, Alex J Clark, David L H Bennett, Mary M Reilly, Linda Greensmith, Bernadett Kalmar
Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which causes the production of atypical deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in blood of HSN-1 patients and this is thought to cause the peripheral motor and sensory nerve damage that is characteristic of the disease, by a largely unresolved mechanism...
May 17, 2018: Neurobiology of Disease
Alberto Cordella, Paraskevi Krashia, Annalisa Nobili, Annabella Pignataro, Livia La Barbera, Maria Teresa Viscomi, Alessandro Valzania, Flavio Keller, Martine Ammassari-Teule, Nicola Biagio Mercuri, Nicola Berretta, Marcello D'Amelio
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...
May 17, 2018: Neurobiology of Disease
Claire C Homan, Stephen Pederson, Thu-Hien To, Chuan Tan, Sandra Piltz, Mark Corbett, Ernst Wolvetang, Paul Thomas, Lachlan A Jolly, Jozef Gecz
PCDH19-Girls Clustering Epilepsy (PCDH19-GCE) is a childhood epileptic encephalopathy characterised by a spectrum of neurodevelopmental problems. PCDH19-GCE is caused by heterozygous loss-of-function mutations in the X-chromosome gene, Protocadherin 19 (PCDH19) encoding a cell-cell adhesion molecule. Intriguingly, hemizygous males are generally unaffected. As PCDH19 is subjected to random X-inactivation, heterozygous females are comprised of a mosaic of cells expressing either the normal or mutant allele, which is thought to drive pathology...
May 12, 2018: Neurobiology of Disease
Huijie Feng, Suad Khalil, Richard R Neubig, Christos Sidiropoulos
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 with involuntary movements (NEDIM)...
May 11, 2018: Neurobiology of Disease
Judit M Pérez Ortiz, Nissa Mollema, Nicholas Toker, Carolyn J Adamski, Brennon O'Callaghan, Lisa Duvick, Jillian Friedrich, Michael A Walters, Jessica Strasser, Jon E Hawkinson, Huda Y Zoghbi, Christine Henzler, Harry T Orr, Sarita Lagalwar
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...
May 11, 2018: Neurobiology of Disease
Chao J Liu, Orion Rainwater, H Brent Clark, Harry T Orr, Taner Akkin
Spinocerebellar ataxia type 1 (SCA1) is a fatal inherited neurodegenerative disease. 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...
May 10, 2018: Neurobiology of Disease
Evan C Rosenberg, Jocelyn J Lippman-Bell, Marcus Handy, Samantha S Soldan, Sanjay Rakhade, Cristina Hilario-Gomez, Kaitlyn Folweiler, Leah Jacobs, Frances E Jensen
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 CaV 1.2 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) Rett Syndrome...
May 5, 2018: Neurobiology of Disease
Shabeesh Balan, Manabu Toyoshima, Takeo Yoshikawa
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...
May 2, 2018: Neurobiology of Disease
Francis Rodriguez Bambico, Stefano Comai, M S Nageeb Hasan, Joshua Dean Conway, Soroush Darvish-Gane, Clement Hamani, Gabriella Gobbi, José N Nobrega
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 pathology...
May 1, 2018: Neurobiology of Disease
Suryanarayan Biswal, Kalpana Kumari Barhwal, Debashree Das, Richa Dhingra, Nilima Dhingra, Tapas Chanda Nag, Sunil Kumar Hota
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 targets and underlying signaling mechanisms...
April 30, 2018: Neurobiology of Disease
Ping-Yue Pan, Yingbo Zhu, Yuan Shen, Zhenyu Yue
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...
April 30, 2018: Neurobiology of Disease
Ori J Lieberman, Avery F McGuirt, Guomei Tang, David Sulzer
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...
April 27, 2018: Neurobiology of Disease
Anton Malkov, Anton I Ivanov, Svetlana Buldakova, Tatsiana Waseem, Irina Popova, Misha Zilberter, Yuri Zilberter
Brain glucose hypometabolism is an early symptom of acquired epilepsy, its causative mechanism yet unclear. We suggest that a bidirectional positive feedback linking seizures and hypometabolism (hypometabolism induces seizures while seizures disrupt glucose metabolism) may be a primary cause for acquired 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...
April 27, 2018: Neurobiology of Disease
John G Cooper, Su Ji Jeong, Tammy L McGuire, Sripadh Sharma, Wenxia Wang, Swati Bhattacharyya, John Varga, John A Kessler
Gliosis and fibrosis after spinal cord injury (SCI) lead to formation of a scar that is an impediment to axonal regeneration. Fibrotic scarring is characterized by the accumulation of fibronectin, collagen, and fibroblasts at the lesion site. The mechanisms regulating fibrotic scarring after SCI and its effects on axonal elongation and functional recovery are not well understood. 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...
April 26, 2018: Neurobiology of Disease
Hua Wang, Anzari Atik, Tessandra Stewart, Carmen Ginghina, Patrick Aro, Kathleen F Kerr, John Seibyl, Danna Jennings, Poul Henning Jensen, Kenneth Marek, Min Shi, Jing Zhang
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 samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction...
April 26, 2018: Neurobiology of Disease
Michael S Wolf, Hülya Bayır, Patrick M Kochanek, Robert S B Clark
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...
April 25, 2018: Neurobiology of Disease
Gorica Ristic, Joanna R Sutton, Kozeta Libohova, Sokol V Todi
Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat...
April 25, 2018: Neurobiology of Disease
S K Kang, S Ammanuel, S Thodupunuri, D A Adler, M V Johnston, S D Kadam
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...
April 20, 2018: Neurobiology of Disease
Michael Aagaard Andersen, Kenneth Vielsted Christensen, Lassina Badolo, Garrick Paul Smith, Ross Jeggo, Poul Henning Jensen, Kathrine Just Andersen, Florence Sotty
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, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease...
April 19, 2018: Neurobiology of Disease
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