Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients.
Abstract Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) and patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts and 43-controls, we found ~25% of sALS cases (termed sALS-1) are characterized by transsulfuration pathway upregulation, where methionine-derived-homocysteine is channeled into cysteine for glutathione synthesis. sALS-1 fibroblasts selectively exhibited a growth defect under oxidative conditions, fully-rescued by N-acetylcysteine (NAC). [U13C]-g...
Source: Neurobiology of Disease - July 31, 2020 Category: Neurology Authors: Chen Q, Konrad C, Sandhu D, Roychoudhury D, Schwartz BI, Cheng RR, Bredvik K, Kawamata H, Calder EL, Studer L, Fischer SM, Manfredi G, Gross SS Tags: Neurobiol Dis Source Type: research

Neuroinflammation and histone H3 citrullination are increased in X-linked Dystonia Parkinsonism post-mortem prefrontal cortex.
C, Sadri-Vakili G Abstract Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP pr...
Source: Neurobiology of Disease - July 30, 2020 Category: Neurology Authors: Petrozziello T, Mills AN, Vaine CA, Penney EB, Fernandez-Cerado C, Legarda GPA, Velasco-Andrada MS, Acuña PJ, Ang MA, Muñoz EL, Diesta CCE, Macalintal-Canlas R, Acuña-Sunshine G, Ozelius LJ, Sharma N, Bragg DC, Sadri-Vakili G Tags: Neurobiol Dis Source Type: research

It's complicated: The relationship between sleep and Alzheimer's disease in humans.
Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an asymptomatic period of amyloid-β (Aβ) deposition as insoluble extracellular plaque, intracellular tau aggregation, neuronal and synaptic loss, and subsequent cognitive dysfunction and dementia. A growing public health crisis, the worldwide prevalence of AD is expected to rise from 46.8 million individuals affected in 2015 to 131.5 million in 2050. Sleep disturbances have been associated with increased future risk of AD. A bi-directional relationship is hypothesized between sleep and AD with sleep disturbance...
Source: Neurobiology of Disease - July 29, 2020 Category: Neurology Authors: Lucey BP Tags: Neurobiol Dis Source Type: research

Circadian alterations in patients with neurodegenerative diseases: Neuropathological basis of underlying network mechanisms.
Abstract Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness towards these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate ...
Source: Neurobiology of Disease - July 28, 2020 Category: Neurology Authors: Fifel K, Videnovic A Tags: Neurobiol Dis Source Type: research

Neurofibromatosis 1 - Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects.
Abstract As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/- mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-...
Source: Neurobiology of Disease - July 28, 2020 Category: Neurology Authors: Elmadany N, Logiacco F, Buonfiglioli A, Haage V, Wright-Jin EC, Schattenberg A, Papawassiliou R, Kettenmann H, Semtner M, Gutmann DH Tags: Neurobiol Dis Source Type: research

Microglia and astrocyte dysfunction in parkinson's disease.
Abstract While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including Parkinson's disease (PD). Recent studies have identified that PD-associated genes are expressed in glial cells as well as neurons and have crucial roles in microglia and astrocytes. Here, we discuss the role of microglia and astrocytes dysfunction in relation to PD-linked mutations and their implications in PD pathogenesis. A better understanding of microglia and astrocyte functions in PD may provide insights into neurodegeneration and novel ther...
Source: Neurobiology of Disease - July 28, 2020 Category: Neurology Authors: Kam TI, Hinkle JT, Dawson TM, Dawson VL Tags: Neurobiol Dis Source Type: research

Corrigendum to "Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis" [Neurobiology of Disease 136 (2020) 104743].
Corrigendum to "Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis" [Neurobiology of Disease 136 (2020) 104743]. Neurobiol Dis. 2020 Jul 28;:105023 Authors: Stankiewicz TR, Pena C, Bouchard RJ, Linseman DA PMID: 32736842 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - July 28, 2020 Category: Neurology Authors: Stankiewicz TR, Pena C, Bouchard RJ, Linseman DA Tags: Neurobiol Dis Source Type: research

PI3K isoform-selective inhibition in neuron-specific PTEN-deficient mice rescues molecular defects and reduces epilepsy-associated phenotypes.
Abstract Epilepsy affects all ages, races, genders, and socioeconomic groups. In about one third of patients, epilepsy is uncontrolled with current medications, leaving a vast need for improved therapies. The causes of epilepsy are diverse and not always known but one gene mutated in a small subpopulation of patients is phosphatase and tensin homolog (PTEN). Moreover, focal cortical dysplasia, which constitutes a large fraction of refractory epilepsies, has been associated with signaling defects downstream of PTEN. So far, most preclinical attempts to reverse PTEN deficiency-associated neurological deficits have f...
Source: Neurobiology of Disease - July 23, 2020 Category: Neurology Authors: White AR, Tiwari D, MacLeod MC, Danzer SC, Gross C Tags: Neurobiol Dis Source Type: research

Microglia, inflammation and gut microbiota responses in a progressive monkey model of Parkinson's disease: A case series.
We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated w...
Source: Neurobiology of Disease - July 23, 2020 Category: Neurology Authors: Joers V, Masilamoni G, Kempf D, Weiss AR, Rotterman TM, Murray B, Yalcin-Cakmakli G, Voll RJ, Goodman MM, Howell L, Bachevalier J, Green S, Naqib A, Shaikh M, Engen P, Keshavarzian A, Barnum CJ, Nye JA, Smith Y, Tansey MG Tags: Neurobiol Dis Source Type: research

Somatic mutations in neurodegeneration: An update.
Abstract Mosaicism, the presence of genomic differences between cells due to post-zygotic somatic mutations, is widespread in the human body, including within the brain. A role for this in neurodegenerative diseases has long been hypothesised, and technical developments are now allowing the question to be addressed in detail. The rapidly accumulating evidence is discussed in this review, with a focus on recent developments. Somatic mutations of numerous types may occur, including single nucleotide variants (SNVs), copy number variants (CNVs), and retrotransposon insertions. They could act as initiators or risk fac...
Source: Neurobiology of Disease - July 23, 2020 Category: Neurology Authors: Proukakis C Tags: Neurobiol Dis Source Type: research

Lentiviral delivery of human erythropoietin attenuates hippocampal atrophy and improves cognition in the R6/2 mouse model of Huntington's disease.
In this study, the therapeutic potential of EPO was evaluated in female R6/2 transgenic mice. A single bilateral injection of a lentivirus encoding human EPO (LV-hEPO) was performed into the lateral ventricles of R6/2 mice at disease onset (8 weeks of age). Control groups were either untreated or injected with a lentivirus encoding green fluorescent protein (LV-GFP). Thirty days after virus administration, hEPO mRNA and protein were present in injected R6/2 brains. Compared to control R6/2 mice, LV-hEPO-treated R6/2 mice exhibited reduced hippocampal atrophy, increased neuroblast branching towards the dentate granular ce...
Source: Neurobiology of Disease - July 20, 2020 Category: Neurology Authors: Rolfes S, Munro DAD, Lyras EM, Matute E, Ouk K, Harms C, Böttcher C, Priller J Tags: Neurobiol Dis Source Type: research

Structure and function of the perivascular fluid compartment and vertebral venous plexus: Illumining a novel theory on mechanisms underlying the pathogenesis of Alzheimer's, cerebral small vessel, and neurodegenerative diseases.
Abstract Blood dynamically and richly supplies the cerebral tissue via microvessels invested in pia matter perforating the cerebral substance. Arteries penetrating the cerebral substance derive an investment from one or two successive layers of pia mater, luminally apposed to the pial-glial basal lamina of the microvasculature and abluminally apposed to a series of aquaporin IV-studded astrocytic end feet constituting the soi-disant glia limitans. The full investment of successive layers forms the variably continuous walls of the periarteriolar, pericapillary, and perivenular divisions of the perivascular fluid co...
Source: Neurobiology of Disease - July 17, 2020 Category: Neurology Authors: Ghali MGZ, Marchenko V, Yaşargil MG, Ghali GZ Tags: Neurobiol Dis Source Type: research

Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus.
ng R, Birkenfeld AL, Löscher W Abstract In addition to tissues such as liver, the plasma membrane sodium-dependent citrate transporter, NaCT (SLC13A5), is highly expressed in brain neurons, but its function is not understood. Loss-of-function mutations in the human SLC13A5 gene have been associated with severe neonatal encephalopathy and pharmacoresistant seizures. The molecular mechanisms of these neurological alterations are not clear. We performed a detailed examination of a Slc13a5 deletion mouse model including video-EEG monitoring, behavioral tests, and electrophysiologic, proteomic, and metabolomic ana...
Source: Neurobiology of Disease - July 16, 2020 Category: Neurology Authors: Henke C, Töllner K, van Dijk RM, Miljanovic N, Cordes T, Twele F, Bröer S, Ziesak V, Rohde M, Hauck SM, Vogel C, Welzel L, Schumann T, Willmes DM, Kurzbach A, El-Agroudy NN, Bornstein SR, Schneider SA, Jordan J, Potschka H, Metallo CM, Köhling R, Birke Tags: Neurobiol Dis Source Type: research

Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
r CCJ Abstract Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitoc...
Source: Neurobiology of Disease - July 16, 2020 Category: Neurology Authors: Lau DHW, Paillusson S, Hartopp N, Rupawala H, Mórotz GM, Gomez-Suaga P, Greig J, Troakes C, Noble W, Miller CCJ Tags: Neurobiol Dis Source Type: research

Passive immunotherapies targeting A β and tau in Alzheimer's disease.
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease. Neurobiol Dis. 2020 Jul 16;:105010 Authors: Plotkin SS, Cashman NR Abstract Amyloid-β (Aβ) and tau proteins currently represent the two most promising targets to treat Alzheimer's disease. The most extensively developed method to treat the pathologic forms of these proteins is through the administration of exogenous antibodies, or passive immunotherapy. In this review, we discuss the molecular-level strategies that researchers are using to design an effective therapeutic antibody, given the challenges in treating this ...
Source: Neurobiology of Disease - July 16, 2020 Category: Neurology Authors: Plotkin SS, Cashman NR Tags: Neurobiol Dis Source Type: research

Local field potential activity dynamics in response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease.
Abstract Local field potentials (LFPs) may afford insight into the mechanisms of action of deep brain stimulation (DBS) and potential feedback signals for adaptive DBS. In Parkinson's disease (PD) DBS of the subthalamic nucleus (STN) suppresses spontaneous activity in the beta band and drives evoked resonant neural activity (ERNA). Here, we investigate how STN LFP activities change over time following the onset and offset of DBS. To this end we recorded LFPs from the STN in 14 PD patients during long (mean: 181.2 s) and short (14.2 s) blocks of continuous stimulation at 130 Hz. LFP activities were evaluated ...
Source: Neurobiology of Disease - July 15, 2020 Category: Neurology Authors: Wiest C, Tinkhauser G, Pogosyan A, Bange M, Muthuraman M, Groppa S, Baig F, Mostofi A, Pereira EA, Tan H, Brown P, Torrecillos F Tags: Neurobiol Dis Source Type: research

Dopamine D1-D2 receptor heteromer expression in key brain regions of rat and higher species: Upregulation in rat striatum after cocaine administration.
CONCLUSION: The dopamine D1-D2 heteromer is expressed in key brain cortical and subcortical regions of all species examined. Species differences in striatum revealed greater abundance in human>nonhuman-primate>rat>mouse, suggesting an evolutionary biologic role for the D1-D2 heteromer in higher CNS function. Its upregulation in rat striatum following cocaine points to regulatory significance with possible relevance for clinical disorders such as drug addiction. The dopamine D1-D2 receptor heteromer may represent a potential target for neuropsychiatric and neurodegenerative disorders, given its distribution in high...
Source: Neurobiology of Disease - July 14, 2020 Category: Neurology Authors: Hasbi A, Sivasubramanian M, Milenkovic M, Komarek K, Madras BK, George SR Tags: Neurobiol Dis Source Type: research

The role of glia in protein aggregation.
Abstract Protein aggregation diseases involve intracellular accumulation or extracellular deposition of certain protein species in neuronal or glial cells, leading to neurodegeneration and shortened lifespan. Prime examples include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), which are affected by overlapping or specific aggregation-prone proteins. Mounting evidence suggests that dysfunctional glial cells may be major drivers for some diseases, and when they are not causal factors, they could still significantly exacerbate or alleviate dise...
Source: Neurobiology of Disease - July 11, 2020 Category: Neurology Authors: Li Q, Haney MS Tags: Neurobiol Dis Source Type: research

Comparative analysis of alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism ATP1A3 mutations reveals functional deficits, which do not correlate with disease severity.
ewich H Abstract Heterozygous mutations in the ATP1A3 gene, coding for an alpha subunit isoform (α3) of Na+/K+-ATPase, are the primary genetic cause for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), early infantile epileptic encephalopathy (EIEE), childhood rapid onset ataxia (CROA) and relapsing encephalopathy with rapid onset ataxia (RECA) extend the clinical spectrum of ATP1A3 related disorders. AHC and RDP demonstrate distinct clinical features, with AHC sympto...
Source: Neurobiology of Disease - July 9, 2020 Category: Neurology Authors: Lazarov E, Hillebrand M, Schröder S, Ternka K, Hofhuis J, Ohlenbusch A, Barrantes-Freer A, Pardo LA, Fruergaard MU, Nissen P, Brockmann K, Gärtner J, Rosewich H Tags: Neurobiol Dis Source Type: research

Modeling UBQLN2-mediated neurodegenerative disease in mice: Shared and divergent properties of wild type and mutant UBQLN2 in phase separation, subcellular localization, altered proteostasis pathways, and selective cytotoxicity.
Abstract The ubiquitin-binding proteasomal shuttle protein UBQLN2 is implicated in common neurodegenerative disorders due to its accumulation in disease-specific aggregates and, when mutated, directly causes familial frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). Like other proteins linked to FTD/ALS, UBQLN2 undergoes phase separation to form condensates. The relationship of UBQLN2 phase separation and accumulation to neurodegeneration, however, remains uncertain. Employing biochemical, neuropathological and behavioral assays, we studied the impact of overexpressing WT or mutant UBQLN2 in the CNS...
Source: Neurobiology of Disease - July 9, 2020 Category: Neurology Authors: Sharkey LM, Sandoval-Pistorius SS, Moore SJ, Gerson JE, Komlo R, Fischer S, Negron-Rios KY, Crowley EV, Padron F, Patel R, Murphy GG, Paulson HL Tags: Neurobiol Dis Source Type: research

Progressive tau aggregation does not alter functional brain network connectivity in seeded hTau.P301L mice.
Abstract Progressive accumulation of hyperphosphorylated tau is a hallmark of various neurodegenerative disorders including Alzheimer's disease. However, to date, the functional effects of tau pathology on brain network connectivity have been investigated to a limited extent. To directly interrogate the impact of tau pathology on functional brain connectivity, we conducted a longitudinal experiment in which we monitored a seeded hTau.P301L mouse model using correlative whole-brain microscopy and resting-state functional MRI. Despite a progressive aggravation of tau pathology across the brain, the major resting-sta...
Source: Neurobiology of Disease - July 9, 2020 Category: Neurology Authors: Detrez JR, Ben-Nejma IRH, Van Kolen K, Van Dam D, De Deyn PP, Fransen E, Verhoye M, Timmermans JP, Nuydens R, Van der Linden A, Keliris GA, De Vos WH Tags: Neurobiol Dis Source Type: research

Ceramide signalling in inherited and multifactorial brain metabolic diseases.
Abstract In recent years, research on sphingolipids, particularly ceramides, has attracted increased attention, revealing the important roles and many functions of these molecules in several human neurological disorders. The nervous system is enriched with important classes of sphingolipids, e.g., ceramide and its derivatives, which compose the major portion of this group, particularly in the form of myelin. Ceramides have also emerged as important nodes for lipid signalling, both inside the cell and between cells. Until recently, knowledge about ceramides in the nervous system was limited, but currently, multiple...
Source: Neurobiology of Disease - July 9, 2020 Category: Neurology Authors: Pant DC, Aguilera-Albesa S, Pujol A Tags: Neurobiol Dis Source Type: research

Neddylation activity modulates the neurodegeneration associated with fragile X associated tremor/ataxia syndrome (FXTAS) through regulating Sima.
Abstract Fragile X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansion of CGG repeats in the 5' UTR of the fragile X mental retardation 1 (FMR1) gene. Using the well-established FXTAS Drosophila model, we performed a high-throughput chemical screen using 3200 small molecules. NSC363998 was identified to suppress the neurodegeneration caused by riboCGG (rCGG) repeats. Three predicted targets of a NSC363998 derivative are isopeptidases in the neddylation pathway and could modulate the neurotoxicity caused by the rCGG repeats. Decreasing levels of neddylation resul...
Source: Neurobiology of Disease - July 9, 2020 Category: Neurology Authors: Lin Y, Xue J, Deng J, He H, Luo S, Chen J, Li J, Yu L, Zhao J, Chen J, Allen EG, Jin P, Duan R Tags: Neurobiol Dis Source Type: research

Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.
In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally R6/2 HD mice. Our findings indicate for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the...
Source: Neurobiology of Disease - July 4, 2020 Category: Neurology Authors: Di Pardo A, Pepe G, Capocci L, Marracino F, Amico E, Del Vecchio L, Giova S, Jeong SK, Park BM, Park BD, Maglione V Tags: Neurobiol Dis Source Type: research

Glia: victims or villains of the aging brain?
Abstract Aging is the strongest risk factor for metabolic, vascular and neurodegenerative diseases. Aging alone is associated with a gradual decline of cognitive and motor functions. Considering an increasing elderly population in the last century, understanding the cellular and molecular mechanisms contributing to brain aging is of vital importance. Recent genetic and transcriptomic findings strongly suggest that glia are the first cells changing with aging. Glial cells constitute around 50% of the total cells in the brain and play key roles regulating brain homeostasis in health and disease. Their essential func...
Source: Neurobiology of Disease - July 2, 2020 Category: Neurology Authors: Salas IH, Burgado J, Allen NJ Tags: Neurobiol Dis Source Type: research

The investigation of the T-type calcium channel enhancer SAK3 in an animal model of TAF1 intellectual disability syndrome.
Abstract T-type calcium channels, in the central nervous system, are involved in the pathogenesis of many neurodegenerative diseases, including TAF1 intellectual disability syndrome (TAF1 ID syndrome). Here, we evaluated the efficacy of a novel T-type Ca2+ channel enhancer, SAK3 (ethyl 8'-methyl-2', 4-dioxo-2-(piperidin-1-yl)-2'H-spiro [cyclopentane-1, 3'-imidazo [1, 2-a] pyridine]-2-ene-3-carboxylate) in an animal model of TAF1 ID syndrome. At post-natal day 3, rat pups were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 CRISPR/Cas9 viruses. At post-natal day 21 animals w...
Source: Neurobiology of Disease - July 1, 2020 Category: Neurology Authors: Janakiraman U, Dhanalakshmi C, Yu J, Moutal A, Boinon L, Fukunaga K, Khanna R, Nelson MA Tags: Neurobiol Dis Source Type: research

Neurobiology of coronaviruses: Potential relevance for COVID-19.
Abstract In the first two decades of the 21st century, there have been three outbreaks of severe respiratory infections caused by highly pathogenic coronaviruses (CoVs) around the world: the severe acute respiratory syndrome (SARS) by the SARS-CoV in 2002-2003, the Middle East respiratory syndrome (MERS) by the MERS-CoV in June 2012, and Coronavirus Disease 2019 (COVID-19) by the SARS-CoV-2 presently affecting most countries In all of these, fatalities are a consequence of a multiorgan dysregulation caused by pulmonary, renal, cardiac, and circulatory damage; however, COVID patients may show significant neurologic...
Source: Neurobiology of Disease - July 1, 2020 Category: Neurology Authors: Cataldi M, Pignataro G, Taglialatela M Tags: Neurobiol Dis Source Type: research

REM sleep behavior disorder (RBD).
Abstract Since its first description in 1986 by Dr. Carlos Schenck, and his group's subsequent report of the delayed emergence of a Parkinsonian disorder in idiopathic RBD patients one decade later, RBD has emerged in recent years as one of the most promising markers of prodromal Parkinson's (References 2, 3). RBD is present in 25-58% of patients with Parkinson's disease and up to 90% of those with Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA). In a substantial proportion of these patients RBD onset occurs before motor symptoms. Critically, when seen in isolation, RBD is a highly specific marker...
Source: Neurobiology of Disease - June 26, 2020 Category: Neurology Authors: Hu MT Tags: Neurobiol Dis Source Type: research

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis.
zado MA, Muñoz E Abstract Multiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/Cannabinoid receptor type 2 (PPARγ/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulat...
Source: Neurobiology of Disease - June 26, 2020 Category: Neurology Authors: Navarrete C, García-Martin A, Garrido-Rodríguez M, Mestre L, Feliú A, Guaza C, Calzado MA, Muñoz E Tags: Neurobiol Dis Source Type: research

The contribution of glial cells to Huntington's disease pathogenesis.
Abstract Glial cells play critical roles in the normal development and function of neural circuits, but in many neurodegenerative diseases, they become dysregulated and may contribute to the development of brain pathology. In Huntington's disease (HD), glial cells both lose normal functions and gain neuropathic phenotypes. In addition, cell-autonomous dysfunction elicited by mutant huntingtin (mHTT) expression in specific glial cell types is sufficient to induce both pathology and Huntington's disease-related impairments in motor and cognitive performance, suggesting that these cells may drive the development of c...
Source: Neurobiology of Disease - June 25, 2020 Category: Neurology Authors: Wilton DK, Stevens B Tags: Neurobiol Dis Source Type: research

GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming.
Abstract Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or pallidal deep brain stimulation, suggesting that the medial globus pallidus plays a significant role in the development of L-DOPA-induced dyskinesia. In the present study, the pathological changes of the medial globus pallidus in L-DOPA-induced dyskinesia were studied in rat models of Parkinson's disease (unilatera...
Source: Neurobiology of Disease - June 23, 2020 Category: Neurology Authors: Nishijima H, Mori F, Arai A, Zhu G, Wakabayashi K, Okada M, Ueno S, Ichinohe N, Suzuki C, Kon T, Tomiyama M Tags: Neurobiol Dis Source Type: research

Delayed administration of the human anti-RGMa monoclonal antibody elezanumab promotes functional recovery including spontaneous voiding after spinal cord injury in rats.
Abstract Spinal cord injury (SCI) often results in permanent functional loss due to a series of degenerative events including cell death, axonal damage, and the upregulation of inhibitory proteins that impede regeneration. Repulsive Guidance Molecule A (RGMa) is a potent inhibitor of axonal growth that is rapidly upregulated following injury in both the rodent and human central nervous system (CNS). Previously, we showed that monoclonal antibodies that specifically block inhibitory RGMa signaling promote neuroprotective and regenerative effects when administered acutely in a clinically relevant rat model of thorac...
Source: Neurobiology of Disease - June 23, 2020 Category: Neurology Authors: Mothe AJ, Coelho M, Huang L, Monnier PP, Cui YF, Mueller BK, Jacobson PB, Tator CH Tags: Neurobiol Dis Source Type: research

Corrigendum to "DJ-1 can form β-sheet structured aggregates that co-localize with pathological amyloid deposits". Neurobiology of Disease 134 (2020) 104629.
Corrigendum to "DJ-1 can form β-sheet structured aggregates that co-localize with pathological amyloid deposits". Neurobiology of Disease 134 (2020) 104629. Neurobiol Dis. 2020 Jun 20;:104971 Authors: Solti K, Kuan WL, Fórizs B, Kustos G, Mihály J, Varga Z, Herberth B, Moravcsik É, Kiss R, Kárpáti M, Mikes A, Zhao Y, Imre T, Rochet JC, Aigbirhio F, Williams-Gray CH, Barker RA, Tóth G PMID: 32576487 [PubMed - as supplied by publisher] (Source: Neurobiology of Disease)
Source: Neurobiology of Disease - June 20, 2020 Category: Neurology Authors: Solti K, Kuan WL, Fórizs B, Kustos G, Mihály J, Varga Z, Herberth B, Moravcsik É, Kiss R, Kárpáti M, Mikes A, Zhao Y, Imre T, Rochet JC, Aigbirhio F, Williams-Gray CH, Barker RA, Tóth G Tags: Neurobiol Dis Source Type: research

DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons.
Abstract Mutations in the DEPDC5 gene can cause epilepsy, including forms with and without brain malformations. The goal of this study was to investigate the contribution of DEPDC5 gene dosage to the underlying neuropathology of DEPDC5-related epilepsies. We generated induced pluripotent stem cells (iPSCs) from epilepsy patients harboring heterozygous loss of function mutations in DEPDC5. Patient iPSCs displayed increases in both phosphorylation of ribosomal protein S6 and proliferation rate, consistent with elevated mTORC1 activation. In line with these findings, we observed increased soma size in patient iPSC-de...
Source: Neurobiology of Disease - June 20, 2020 Category: Neurology Authors: Klofas LK, Short BP, Snow JP, Sinnaeve J, Rushing GV, Westlake G, Weinstein W, Ihrie RA, Ess KC, Carson RP Tags: Neurobiol Dis Source Type: research

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants.
This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). METHODS: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (
Source: Neurobiology of Disease - June 20, 2020 Category: Neurology Authors: Miller JB, Ward E, Staley LA, Stevens J, Teerlink CC, Tavana JP, Cloward M, Page M, Dayton L, Alzheimer's Disease Genetics Consortium, Cannon-Albright LA, Kauwe JSK Tags: Neurobiol Dis Source Type: research

Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study.
Abstract Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein (FMRP), a putative translation suppressor, is absent or significantly reduced in FXS. One prevailing hypothesis is that rates of protein synthesis are increased by the absence of this regulatory protein. In accord with this hypothesis, we have previously reported increased rates of cerebral protein synthesis (rCPS) in the Fmr1 knockout mouse model of FXS and others have reported similar effects in hippocampal slices. To address the hypothesis in human subjects, we applied the L[1-11...
Source: Neurobiology of Disease - June 19, 2020 Category: Neurology Authors: Schmidt KC, Loutaev I, Quezado Z, Sheeler C, Smith CB Tags: Neurobiol Dis Source Type: research

Genetic risk factors for Creutzfeldt-Jakob disease.
Abstract Prion diseases are a group of fatal neurodegenerative disorders of mammals that share a central role for prion protein (PrP, gene PRNP) in their pathogenesis. Prions are infectious agents that account for the observed transmission of prion diseases between humans and animals in certain circumstances. The prion mechanism invokes a misfolded and multimeric assembly of PrP (a prion) that grows by templating of the normal protein and propagates by fission. Aside from the medical and public health notoriety of acquired prion diseases, the conditions have attracted interest as it has been realized that common n...
Source: Neurobiology of Disease - June 18, 2020 Category: Neurology Authors: Jones E, Mead S Tags: Neurobiol Dis Source Type: research

Genetic architecture of Alzheimer's disease.
Abstract Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell an...
Source: Neurobiology of Disease - June 18, 2020 Category: Neurology Authors: Neuner SM, Tcw J, Goate AM Tags: Neurobiol Dis Source Type: research

Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience.
Abstract Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were as...
Source: Neurobiology of Disease - June 16, 2020 Category: Neurology Authors: Tsur SR, Demiray YE, Tripathi K, Stork O, Richter-Levin G, Albrecht A Tags: Neurobiol Dis Source Type: research

The environmental toxicant ziram enhances neurotransmitter release and increases neuronal excitability via the EAG family of potassium channels.
Abstract Environmental toxicants have the potential to contribute to the pathophysiology of multiple complex diseases, but the underlying mechanisms remain obscure. One such toxicant is the widely used fungicide ziram, a dithiocarbamate known to have neurotoxic effects and to increase the risk of Parkinson's disease. We have used Drosophila melanogaster as an unbiased discovery tool to identify novel molecular pathways by which ziram may disrupt neuronal function. Consistent with previous results in mammalian cells, we find that ziram increases the probability of synaptic vesicle release by dysregulation of the ub...
Source: Neurobiology of Disease - June 15, 2020 Category: Neurology Authors: Harrigan J, Brambila DF, Meera P, Krantz DE, Schweizer FE Tags: Neurobiol Dis Source Type: research

Shifting paradigms: The central role of microglia in Alzheimer's disease.
Abstract Recent human genetic studies have challenged long standing hypotheses about the chain of events in Alzheimer's disease (AD), as the identification of genetic risk factors in microglial genes supports a causative role for microglia in the disease. Parallel transcriptome and histology studies at the single-cell level revealed a rich palette of microglial states affected by disease status and genetic risk factors. Taken together, those findings support microglia dysfunction as a central mechanism in AD etiology and thus the therapeutic potential of modulating microglial activity for AD treatment. Here we rev...
Source: Neurobiology of Disease - June 11, 2020 Category: Neurology Authors: Schwabe T, Srinivasan K, Rhinn H Tags: Neurobiol Dis Source Type: research

ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain.
We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of...
Source: Neurobiology of Disease - June 9, 2020 Category: Neurology Authors: Mitchell R, Mikolajczak M, Kersten C, Fleetwood-Walker S Tags: Neurobiol Dis Source Type: research

Why Woody got the blues: The neurobiology of depression in Huntington's disease.
Abstract Huntington's disease (HD) is an extraordinary disorder that usually strikes when individuals are in the prime of their lives, as was the case for the influential 20th century musician Woody Guthrie. HD demonstrates the exceptionally fine line between life and death in such 'genetic diseases', as the only difference between those who suffer horribly and die slowly of this disease is often just a handful of extra tandem repeats (beyond the normal polymorphic range) in a genome that constitutes over 3 billion paired nucleotides of DNA. Furthermore, HD presents as a complex and heterogenous combination of psy...
Source: Neurobiology of Disease - June 8, 2020 Category: Neurology Authors: Gubert C, Renoir T, Hannan AJ Tags: Neurobiol Dis Source Type: research

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.
K, Joseph-Mathurin N, Karch CM, Koeppe RA, Lee AKW, Levin J, Masters C, McDade E, Perrin RJ, Rowe CC, Salloway S, Saykin AJ, Sperling R, Su Y, Villemagne VL, Vöglein J, Weiner M, Xiong C, Fagan AM, Morris JC, Bateman RJ, Benzinger TLS, Jucker M, Gordon BA, Dominantly Inherited Alzheimer Network Abstract Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the conc...
Source: Neurobiology of Disease - June 6, 2020 Category: Neurology Authors: Schultz SA, Strain JF, Adedokun A, Wang Q, Preische O, Kuhle J, Flores S, Keefe S, Dincer A, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal J, Cruchaga C, Ewers M, Fox NN, Ghetti B, Goate A, Graff-Radford NR, Hassenstab JJ, Hornbeck R, Jack C, Johnso Tags: Neurobiol Dis Source Type: research

Glia in neurodegeneration: Drivers of disease or along for the ride?
Abstract While much of the research on neurodegenerative diseases has focused on neurons, non-neuronal cells are also affected. The extent to which glia and other non-neuronal cells are causally involved in disease pathogenesis versus more passively responding to disease is an area of active research. This is complicated by the fact that there is rarely one known cause of neurodegenerative diseases; rather, these disorders likely involve feedback loops that perpetuate dysfunction. Here, we will review genetic as well as experimental evidence that suggest that non-neuronal cells are at least partially driving disea...
Source: Neurobiology of Disease - June 5, 2020 Category: Neurology Authors: Gleichman AJ, Carmichael ST Tags: Neurobiol Dis Source Type: research

Disrupted inhibitory plasticity and homeostasis in Fragile X syndrome.
Abstract Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall deficiency in proper sensory circuit coding leading to hyperexcitable sensory networks. However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Here, we show that in vivo layer 2/3 of the primary somatosensory cortex of the Fmr1 KO mouse exhibits basal hyperexci...
Source: Neurobiology of Disease - June 5, 2020 Category: Neurology Authors: Rio CAC, Nunez-Parra A, Freedman S, Kushner JK, Alexander AL, Restrepo D, Huntsman MM Tags: Neurobiol Dis Source Type: research

Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.
Abstract Alzheimer's disease (AD) is a prominent neurodegenerative disorder characterized by deposition of β-amyloid (Aβ)-containing extracellular plaques, accompanied by a microglial-mediated inflammatory response, that leads to cognitive decline. Microglia perform many disease-modifying functions such as phagocytosis of plaques, plaque compaction, and modulation of inflammation through the secretion of cytokines. Microglia are reliant upon colony-stimulating factor receptor-1 (CSF1R) activation for survival. In AD mouse models, chronic targeted depletion of microglia via CSF1R antagonism attenuates pla...
Source: Neurobiology of Disease - May 29, 2020 Category: Neurology Authors: Casali BT, MacPherson KP, Reed-Geaghan EG, Landreth GE Tags: Neurobiol Dis Source Type: research

Prion protein post-translational modifications modulate heparan sulfate binding and limit aggregate size in prion disease.
Abstract Many aggregation-prone proteins linked to neurodegenerative disease are post-translationally modified during their biogenesis. In vivo pathogenesis studies have suggested that the presence of post-translational modifications can shift the aggregate assembly pathway and profoundly alter the disease phenotype. In prion disease, the N-linked glycans and GPI-anchor on the prion protein (PrP) impair fibril assembly. However, the relevance of the two glycans to aggregate structure and disease progression remains unclear. Here we show that prion-infected knockin mice expressing an additional PrP glycan (tri-glyc...
Source: Neurobiology of Disease - May 23, 2020 Category: Neurology Authors: Callender JA, Sevillano AM, Soldau K, Kurt TD, Schumann T, Pizzo DP, Altmeppen H, Glatzel M, Esko JD, Sigurdson CJ Tags: Neurobiol Dis Source Type: research

CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons ameliorates epileptic and behavioral phenotypes of Dravet syndrome model mice.
Abstract Dravet syndrome is a severe infantile-onset epileptic encephalopathy which begins with febrile seizures and is caused by heterozygous loss-of-function mutations of the voltage-gated sodium channel gene SCN1A. We designed a CRISPR-based gene therapy for Scn1a-haplodeficient mice using multiple guide RNAs (gRNAs) in the promoter regions together with the nuclease-deficient Cas9 fused to transcription activators (dCas9-VPR) to trigger the transcription of SCN1A or Scn1a in vitro. We tested the effect of this strategy in vivo using an adeno-associated virus (AAV) mediated system targeting inhibitory neurons a...
Source: Neurobiology of Disease - May 20, 2020 Category: Neurology Authors: Yamagata T, Raveau M, Kobayashi K, Miyamoto H, Tatsukawa T, Ogiwara I, Itohara S, Hensch TK, Yamakawa K Tags: Neurobiol Dis Source Type: research

Polygenic risk and pleiotropy in neurodegenerative diseases.
Abstract In this paper we explore the phenomenon of pleiotropy in neurodegenerative diseases, focusing on Alzheimer's disease (AD). We summarize the various techniques developed to investigate pleiotropy among traits, elaborating in the polygenic risk scores (PRS) analysis. PRS was designed to assess a cumulative effect of a large number of SNPs for association with a disease and, later for disease risk prediction. Since genetic predictions rely on heritability, we discuss SNP-based heritability from genome-wide association studies and its contribution to the prediction accuracy of PRS. We review work examining pl...
Source: Neurobiology of Disease - May 20, 2020 Category: Neurology Authors: Bellou E, Stevenson-Hoare J, Escott-Price V Tags: Neurobiol Dis Source Type: research