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Prion Diseases

Enrico Bagnoli, Una FitzGerald
The olfactory bulb (OB) is often affected at very early stages of neurodegenerative disorders, in the so-called 'prodromal' phase. In Parkinson's disease (PD), olfactory disturbances appear years before motor symptoms arise. Additionally, pathological alpha-synuclein aggregates are found in olfactory regions before spreading to other areas of the brain. Being positioned at the frontier between the brain and a potentially hostile environment, could explain the particular vulnerability of the OB. Mitral cells (MCs), the principal projecting neurons of the olfactory system, are involved in the pathogenesis and in the prion-like progression of PD...
August 18, 2018: European Journal of Neuroscience
Maria Elena Cicardi, Riccardo Cristofani, Paola Rusmini, Marco Meroni, Veronica Ferrari, Giulia Vezzoli, Barbara Tedesco, Margherita Piccolella, Elio Messi, Mariarita Galbiati, Alessandra Boncoraglio, Serena Carra, Valeria Crippa, Angelo Poletti
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motoneurons, while non-neuronal cells may contribute to disease onset and progression. Most ALS cases are characterized by the mislocalization and aggregation of the TAR DNA binding protein 43 (TDP-43) in affected cells. TDP-43 aggregates contain C-terminal TDP-43 fragments of 35 kDa (TDP-35) and 25 kDa (TDP-25) and have been mainly studied in motoneurons, while little is currently known about their rate of accumulation and clearance in myoblasts...
August 17, 2018: Scientific Reports
Paul Lemarre, Laurent Pujo-Menjouet, Suzanne S Sindi
Prions are proteins capable of adopting misfolded conformations and transmitting these conformations to other normally folded proteins. Prions are most commonly known for causing fatal neurodegenerative diseases in mammals but are also associated with several harmless phenotypes in yeast. A distinct feature of prion propagation is the existence of different phenotypical variants, called strains. It is widely accepted that these strains correspond to different conformational states of the protein, but the mechanisms driving their interactions remain poorly understood...
August 16, 2018: Journal of Mathematical Biology
S A Kozin, V I Polshakov, Y V Mezentsev, A S Ivanov, S S Zhokhov, M M Yurinskaya, M G Vinokurov, A A Makarov, V A Mitkevich
Intact amyloid-β peptides (Aβ) may undergo prion-like aggregation when they interact with chemically or structurally modified variants of Aβ present in extracellular pathohistological inclusions (amyloid plaques). This aggregation is regarded as one of the key molecular mechanisms of Alzheimer's disease (AD) pathogenesis. Zinc ions are involved in the pathological dimerization and oligomerization of natural Aβ isoforms, and zinc-induced oligomers can also initiate the pathological aggregation of Aβ. Based on the earlier found molecular mechanism of zinc-dependent oligomerization of Aβ, it has been suggested that the targeted inhibition of the 11EVHH14 site in one Aβ molecule from zinc-mediated interactions with the same site of another Aβ molecule can effectively inhibit the oligomerization and aggregation of Aβ...
July 2018: Molekuliarnaia Biologiia
Ignazio Cali, Fadi Mikhail, Kefeng Qin, Crystal Gregory, Ani Solanki, Manuel Camacho Martinez, Lili Zhao, Brian Appleby, Pierluigi Gambetti, Eric Norstrom, James A Mastrianni
Objective: To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP -G114V variant. Methods: We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease. Results: A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later...
August 2018: Neurology. Genetics
Yufang Yang, Mo Wang, Ping Yang, Zishan Wang, Li Huang, Jing Xu, Wei Wang, Mei Yu, Liping Bu, Jian Fei, Fang Huang
Background : The deposition of β-sheet rich amyloid in senile plaques is a pathological hallmark of Alzheimer's disease (AD), which is thought to cause neuronal dysfunction. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated β-amyloid (Aβ) is able to induce cerebral amyloidosis thus causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption...
2018: Frontiers in Aging Neuroscience
Caterina Masaracchia, Marilena Hnida, Ellen Gerhardt, Tomás Lopes da Fonseca, Anna Villar-Pique, Tiago Branco, Markus A Stahlberg, Camin Dean, Claudio O Fernández, Ira Milosevic, Tiago F Outeiro
Alpha-synuclein (aSyn) plays a crucial role in Parkinson's disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies...
August 14, 2018: Acta Neuropathologica Communications
Michaeline L Hebron, Monica Javidnia, Charbel E-H Moussa
Tau hyperphosphorylation is a critical factor in neurodegenerative diseases, including dementia and Parkinsonism. Existing animal models of tauopathies express tau in neurons within the forebrain and do not often show tau accumulation in the brainstem and astrocytes. This study aims to understand the effects of differential regional expression of tau on neurotransmitter balance in the brain. To obtain an animal model that expresses tau in the brainstem, we bred hemizygous mice that express P301L tau (TauP301L) and detected hyper-phosphorylated tau (p-tau) predominantly in the hippocampus, cortex, brainstem and thalamus...
August 15, 2018: Journal of the Neurological Sciences
Mohammed Helal, Angélique Igel-Egalon, Abdelkader Lakmeche, Pauline Mazzocco, Angélique Perrillat-Mercerot, Laurent Pujo-Menjouet, Human Rezaei, Léon M Tine
Alzheimer's disease (AD) is a neuro-degenerative disease affecting more than 46 million people worldwide in 2015. AD is in part caused by the accumulation of A[Formula: see text] peptides inside the brain. These can aggregate to form insoluble oligomers or fibrils. Oligomers have the capacity to interact with neurons via membrane receptors such as prion proteins ([Formula: see text]). This interaction leads [Formula: see text] to be misfolded in oligomeric prion proteins ([Formula: see text]), transmitting a death signal to neurons...
August 11, 2018: Journal of Mathematical Biology
Olivia Behaeghe, Elias Mangelschots, Bart De Vil, Patrick Cras
BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is a human prion disease that is a relatively common differential diagnosis in dementia patients. Therefore it needs a good diagnostic tool. Brain autopsy is the golden standard for the diagnosis of CJD; however, a less invasive technique is 14-3-3 protein measurement in the cerebrospinal fluid (CSF). In this systematic review, we compared the diagnostic value of the 14-3-3 protein measurement to the newer RT-QuIC test and a variant of RT-QuIC where nasal brushing is used to collect the samples...
August 10, 2018: Acta Neurologica Belgica
Bing Wang, Rachel Underwood, Anjali Kamath, Colleen Britain, Michael B McFerrin, Pamela J McLean, Laura A Volpicelli-Daley, Robert H Whitaker, William J Placzek, Katelyn Becker, Jiyan Ma, Talene A Yacoubian
Alpha-synuclein (αsyn) is the key protein that forms neuronal aggregates in the neurodegenerative disorders Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Recent evidence points to the prion-like spread of αsyn from one brain region to another. Propagation of αsyn is likely dependent on release, uptake, and misfolding. Under normal circumstances, this highly expressed brain protein functions normally without promoting pathology, yet the underlying endogenous mechanisms that prevent αsyn spread are not understood...
August 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Lisa Michelle Restelli, Björn Oettinghaus, Mark Halliday, Cavit Agca, Maria Licci, Lara Sironi, Claudia Savoia, Jürgen Hench, Markus Tolnay, Albert Neutzner, Alexander Schmidt, Anne Eckert, Giovanna Mallucci, Luca Scorrano, Stephan Frank
Stress adaptation is essential for neuronal health. While the fundamental role of mitochondria in neuronal development has been demonstrated, it is still not clear how adult neurons respond to alterations in mitochondrial function and how neurons sense, signal, and respond to dysfunction of mitochondria and their interacting organelles. Here, we show that neuron-specific, inducible in vivo ablation of the mitochondrial fission protein Drp1 causes ER stress, resulting in activation of the integrated stress response to culminate in neuronal expression of the cytokine Fgf21...
August 7, 2018: Cell Reports
Simote Totauhelotu Foliaki, Victoria Lewis, David Isaac Finkelstein, Victoria Lawson, Harold Arthur Coleman, Matteo Senesi, Abu Mohammed Taufiqual Islam, Feng Chen, Shannon Sarros, Blaine Roberts, Paul Anthony Adlard, Steven John Collins
Although misfolding of normal prion protein (PrPC) into abnormal conformers (PrPSc) is critical for prion disease pathogenesis our current understanding of the underlying molecular pathophysiology is rudimentary. Exploiting an electrophysiology paradigm, herein we report that at least modestly proteinase K (PK)-resistant PrPSc (PrPres) species are acutely synaptotoxic. Brief exposure to ex vivo PrPSc from two mouse-adapted prion strains (M1000 and MU02) prepared as crude brain homogenates (cM1000 and cMU02) and cell lysates from chronically M1000-infected RK13 cells (MoRK13-Inf) caused significant impairment of hippocampal CA1 region long-term potentiation (LTP), with the LTP disruption approximating that reported during the evolution of murine prion disease...
August 8, 2018: PLoS Pathogens
J Obst, R Mancuso, E Simon, D Gomez-Nicola
Chronic inflammation is a major driver of neurodegenerative disease and immune regulatory pathways could be potential targets for therapeutic intervention. Recently, Programmed cell death-1 (PD-1) immune checkpoint inhibition has been proposed to mount an IFN-γ-dependent systemic immune response, leading to the recruitment of peripheral myeloid cells to the brain and neuropathological and functional improvements in mice with Alzheimer's disease- like β-amyloid pathology. Here we investigate the impact of PD-1 deficiency on murine prion disease (ME7 strain), a model of chronic neurodegeneration...
August 4, 2018: Brain, Behavior, and Immunity
Lorna M Gibson, Francesca M Chappell, David Summers, Donald A Collie, Robin Sellar, Jonathan Best, Richard Knight, James W Ironside, Joanna M Wardlaw
The relationship between magnetic resonance imaging (MRI) and clinical variables in patients suspected to have Creutzfeldt-Jakob Disease (CJD) is uncertain. We aimed to determine which MRI features of CJD (positive or negative), previously described in vivo, accurately identify CJD, are most reliably detected, vary with disease duration, and whether combined clinical and imaging features increase diagnostic accuracy for CJD. Prospective patients suspected of having CJD were referred to the National CJD Research and Surveillance Unit between 1994-2004; post-mortem, brains were sent for MRI and histopathology...
2018: PloS One
Yasushi Iwasaki, Kazuhiro Imamura, Katsushige Iwai, Yasushi Kobayashi, Akio Akagi, Maya Mimuro, Hiroaki Miyahara, Tetsuyuki Kitamoto, Mari Yoshida
We present an autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with extensive amyloid-β (Aβ) deposition in the brain. A 39-year-old Japanese woman presented with memory disturbance and abnormal behavior. The patient had a history of craniotomy with dura matter-graft transplant for a head injury which occurred when she was 19 years old. Magnetic resonance imaging (MRI) showed hyperintensities in the cerebral cortex and striatum on diffusion-weighted images, particularly on the dura mater-grafted right side...
August 6, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Eirini Kanata, Katrin Thüne, Konstantinos Xanthopoulos, Isidre Ferrer, Dimitra Dafou, Inga Zerr, Theodoros Sklaviadis, Franc Llorens
Prion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations...
2018: Frontiers in Aging Neuroscience
Emmanuel E Comoy, Jacqueline Mikol, Jean-Philippe Deslys
The recently reevaluated high prevalence of healthy carriers (1/2,000 in UK) of variant Creutzfeldt-Jakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under full control as expected. After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed (human and animal) individuals, we confirmed in these both models the transmissibility of v-CJD, but we also observed unexpected neurological syndromes transmissible by transfusion: despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the absence of detectable abnormal PrP with current techniques...
August 6, 2018: Prion
Kaori Tsukakoshi, Wataru Yoshida, Masaki Kobayashi, Natsuki Kobayashi, Jihoon Kim, Toshisuke Kaku, Toshitsugu Iguchi, Kazuo Nagasawa, Ryutaro Asano, Kazunori Ikebukuro, Koji Sode
Several neurodegenerative diseases have a common pathophysiology where selective damage to neurons results from the accumulation of amyloid oligomer proteins formed via fibrilization. Considering that the formation of amyloid oligomers leads to cytotoxicity, the development of chemical compounds that are able to effectively cross the blood-brain barrier (BBB) and inhibit this conversion to oligomers and/or fibrils is essential for neurodegenerative disease therapy. We previously reported that pyrroloquinoline quinone (PQQ) prevented aggregation and fibrillation of α-synuclein, amyloid β1-42 (Aβ1-42 ), and mouse prion protein...
August 8, 2018: ACS Chemical Neuroscience
Ryo Honda, Kei-Ichi Yamaguchi, Abdelazim Elsayed Elhelaly, Mitsuhiko Fuji, Kazuo Kuwata
Transmissible spongiform encephalopathies (TSEs) are a group of lethal neurodegenerative diseases involving the structural conversion of cellular prion protein (PrPC ) into the pathogenic isoform (PrPSc ) for which no effective treatment is currently available. Previous studies have implicated that a polymeric molecule with a repeating unit, such as pentosane polysulfate and polyamidoamide dendrimers, exhibits a potent anti-prion activity, suggesting that poly-(amino acid)s could be a candidate molecule for inhibiting prion propagation...
August 17, 2018: Prion
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