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Youngsin Jung, Erik K St Louis
REM sleep behavior disorder (RBD) is a common parasomnia disorder affecting between 1 and 7 % of community-dwelling adults, most frequently older adults. RBD is characterized by nocturnal complex motor behavior and polysomnographic REM sleep without atonia. RBD is strongly associated with synucleinopathy neurodegeneration. The approach to RBD management is currently twofold: symptomatic treatment to prevent injury and prognostic counseling and longitudinal follow-up surveillance for phenoconversion toward overt neurodegenerative disorders...
November 2016: Current Treatment Options in Neurology
Graham Fairfoul, Lynne I McGuire, Suvankar Pal, James W Ironside, Juliane Neumann, Sharon Christie, Catherine Joachim, Margaret Esiri, Samuel G Evetts, Michal Rolinski, Fahd Baig, Claudio Ruffmann, Richard Wade-Martins, Michele T M Hu, Laura Parkkinen, Alison J E Green
We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results...
October 2016: Annals of Clinical and Translational Neurology
Hye-Jin Park, Kang-Woo Lee, Eun S Park, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α-Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho-Ser129 phosphatase...
October 2016: Annals of Clinical and Translational Neurology
Neal K Bennett, Rebecca Chmielowski, Dalia S Abdelhamid, Jonathan J Faig, Nicola Francis, Jean Baum, Zhiping P Pang, Kathryn E Uhrich, Prabhas V Moghe
Neuroinflammation, a common neuropathologic feature of neurodegenerative disorders including Parkinson disease (PD), is frequently exacerbated by microglial activation. The extracellular protein α-synuclein (ASYN), whose aggregation is characteristic of PD, remains a key therapeutic target, but the control of synuclein trafficking and aggregation within microglia has been challenging. First, we established that microglial internalization of monomeric ASYN was mediated by scavenger receptors (SR), CD36 and SRA1, and was rapidly accompanied by the formation of ASYN oligomers...
December 2016: Biomaterials
Anna Villar-Piqué, Tomás Lopes da Fonseca, Ricardo Sant'Anna, Éva Mónika Szegö, Luis Fonseca-Ornelas, Raquel Pinho, Anita Carija, Ellen Gerhardt, Caterina Masaracchia, Enrique Abad Gonzalez, Giulia Rossetti, Paolo Carloni, Claudio O Fernández, Debora Foguel, Ira Milosevic, Markus Zweckstetter, Salvador Ventura, Tiago Fleming Outeiro
Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors...
October 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xiaobo Mao, Michael Tianhao Ou, Senthilkumar S Karuppagounder, Tae-In Kam, Xiling Yin, Yulan Xiong, Preston Ge, George Essien Umanah, Saurav Brahmachari, Joo-Ho Shin, Ho Chul Kang, Jianmin Zhang, Jinchong Xu, Rong Chen, Hyejin Park, Shaida A Andrabi, Sung Ung Kang, Rafaella Araújo Gonçalves, Yu Liang, Shu Zhang, Chen Qi, Sharon Lam, James A Keiler, Joel Tyson, Donghoon Kim, Nikhil Panicker, Seung Pil Yun, Creg J Workman, Dario A A Vignali, Valina L Dawson, Han Seok Ko, Ted M Dawson
Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity...
September 30, 2016: Science
Daphné Génier Marchand, Jacques Montplaisir, Ronald B Postuma, Shady Rahayel, Jean-François Gagnon
STUDY OBJECTIVES: Long-term studies in REM sleep behavior disorder (RBD) have shown a high rate of conversion into synucleinopathies. We aimed to prospectively follow up a large cohort of RBD patients to identify cognitive markers for early detection of prodromal dementia. METHODS: Seventy-six idiopathic RBD patients underwent polysomnography and a complete neuropsychological and neurological assessment and were then followed for a mean of 3.6 years. Cognitive characteristics at baseline were compared between patients who remained disease-free and those who developed a synucleinopathy, and between those who developed dementia first and those who developed parkinsonism first...
September 26, 2016: Sleep
Wolfgang Wrasidlo, Igor F Tsigelny, Diana L Price, Garima Dutta, Edward Rockenstein, Thomas C Schwarz, Karin Ledolter, Douglas Bonhaus, Amy Paulino, Simona Eleuteri, Åge A Skjevik, Valentina L Kouznetsova, Brian Spencer, Paula Desplats, Tania Gonzalez-Ruelas, Margarita Trejo-Morales, Cassia R Overk, Stefan Winter, Chunni Zhu, Marie-Francoise Chesselet, Dieter Meier, Herbert Moessler, Robert Konrat, Eliezer Masliah
Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A...
September 27, 2016: Brain: a Journal of Neurology
Zdenek Rohan, Ivan Milenkovic, Mirjam I Lutz, Radoslav Matej, Gabor G Kovacs
Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25α (TPPP/p25α), α-synuclein (α-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10)...
September 26, 2016: Journal of Neuropathology and Experimental Neurology
Nóra Török, Zsófia Majláth, Levente Szalárdy, László Vécsei
The therapeutic management of Parkinson's disease (PD) is challenging and has not been fully resolved. The main challenges include motor fluctuations and levodopa-induced dyskinesia. Moreover, no disease-modifying or neuroprotective therapy is currently available. Areas covered: This review focuses on α-synuclein aggregation inhibitors and their therapeutic role in PD, with special attention to heat shock proteins, immunotherapy (active and passive), the potential of targeting the Ser129 phosphorylation site, and the antibiotic possibilities...
October 8, 2016: Expert Opinion on Investigational Drugs
Tibor Szénási, Judit Oláh, Adél Szabó, Sándor Szunyogh, András Láng, András Perczel, Attila Lehotzky, Vladimir N Uversky, Judit Ovádi
The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs...
September 23, 2016: Biochimica et Biophysica Acta
Alana Hoffmann, Benjamin Ettle, Ariane Bruno, Anna Kulinich, Anna-Carin Hoffmann, Julia von Wittgenstein, Jürgen Winkler, Wei Xiang, Johannes C M Schlachetzki
Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are defined by the presence of intracellular alpha-synuclein aggregates in neurons and/or oligodendrocytes. In addition, post mortem tissue analysis revealed profound changes in microglial morphology, indicating microglial activation and neuroinflammation. Thus, alpha-synuclein may directly activate microglia, leading to increased production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), which in turn modulates the disease progression...
October 28, 2016: Biochemical and Biophysical Research Communications
Michel Goedert, Masami Masuda-Suzukake, Benjamin Falcon
The abnormal aggregation of a small number of known proteins underlies the most common human neurodegenerative diseases. In tauopathies and synucleinopathies, the normally soluble intracellular proteins tau and α-synuclein become insoluble and filamentous. In recent years, non-cell autonomous mechanisms of aggregate formation have come to the fore, suggesting that nucleation-dependent aggregation may occur in a localized fashion in human tauopathies and synucleinopathies, followed by seed-dependent propagation...
September 21, 2016: Brain: a Journal of Neurology
Michael S Marshall, Ernesto R Bongarzone
New insights into the pathophysiological mechanisms behind late-onset neurodegenerative diseases have come from unexpected sources in recent years. Specifically, the group of inherited metabolic disorders known as lysosomal storage diseases that most commonly affect infants has been found to have surprising similarities with adult neurodegenerative disorders. Most notable has been the identification of Gaucher's disease as a comorbidity for Parkinson's disease. Prompted by the recent identification of neuronal aggregates of α-synuclein in another lysosomal storage disease, Krabbe's disease, we propose the idea that a similar connection exists between adult synucleinopathies and Krabbe's...
November 2016: Journal of Neuroscience Research
R Savica, B F Boeve, G Logroscino
The epidemiology of the diagnosis of Parkinson's disease and dementia with Lewy bodies is still based on clinical criteria and the definition of the different diseases is still a challenge for clinician and researcher. The epidemiologic estimates of prevalence and incidence are highly affected by differences in diagnostic criteria, geographic location, and methodologic limitations. Studies of prevalence and incidence show increases with advancing age and a higher rate of Parkinson's disease and dementia with Lewy bodies in men compared to women...
2016: Handbook of Clinical Neurology
Poul Jørgen Jennum, Lars Østergaard Pedersen, Justyna Maria Czarna Bahl, Signe Modvig, Karina Fog, Anja Holm, Birgitte Rahbek Kornum, Steen Gammeltoft
OBJECTIVES: To investigate whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration are altered in narcolepsy in order to evaluate whether the hypocretin deficiency and abnormal sleep-wake pattern in narcolepsy leads to neurodegeneration. METHODS: Twenty-one patients with central hypersomnia (10 type 1 narcolepsy, 5 type 2 narcolepsy, and 6 idiopathic hypersomnia cases) aged 33 years on average, and with a disease duration of 2-29 years, and 12 healthy controls underwent CSF analyses of levels of β-amyloid, total tau protein (T-tau), phosphorylated tau protein (P-tau181), α-synuclein, neurofilament light chain (NF-L), and chitinase 3-like protein-1 (CHI3L1)...
September 9, 2016: Sleep
Hemi Malkki
No abstract text is available yet for this article.
October 2016: Nature Reviews. Neurology
Xuling Li, Simon James, Peng Lei
Tau and α-Synuclein (α-Syn) are abundant brain proteins with distinct biological functions. Findings suggest that interactions between α-Syn and tau at the cellular level cause disruption of cytoskeletal organization, axonal transport defects, and aberrant synaptic organization. The ability of tau and α-Syn to affect each other directly or indirectly might contribute to the overlap in the clinical and pathological features of tauopathies and synucleinopathies. The interactions between α-Syn and tau, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, still deserve further investigation...
November 2016: Journal of Molecular Neuroscience: MN
Shlomit Yust Katz, Ronly Hershkovitz, Tanya Gurevich, Ruth Djaldetti
OBJECTIVE: Pain is one of the most common non-motor symptoms of Parkinson disease (PD) and other Parkinson plus syndromes, with a major effect on quality of life. The aims of the study were to examine the prevalence and characteristics of pain in PD and other Parkinson plus syndromes and patient use and response to pain medications. METHODS: The cohort consisted of 371 patients: 300 (81%) with PD and 71 (19%) with Parkinson plus syndromes. Data on clinical parameters and pain were collected by questionnaire...
September 10, 2016: Clinical Journal of Pain
Yvette C Wong, Dimitri Krainc
Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GTP-binding protein type A1 (GBA1) gene encoding the lysosomal hydrolase β-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β-glucocerebrosidase activity...
September 13, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
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