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Bradley F. Boeve - One of the best experts on this subject based on the ideXlab platform.
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REM sleep behaviour disorder
Nature reviews Disease primers, 2018Co-Authors: Yves Dauvilliers, Pierre-hervé Luppi, Alex Iranzo, Jacques Montplaisir, Ronald B. Postuma, Carlos Schenck, Bradley F. BoeveAbstract:Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-Synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapies in patients with idiopathic RBD to prevent or delay α-Synucleinopathy-related motor and cognitive decline.
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survival and causes of death among people with clinically diagnosed synucleinopathies with parkinsonism a population based study
JAMA Neurology, 2017Co-Authors: Rodolfo Savica, Bradley F. Boeve, James H. Bower, Brandon R Grossardt, Eric J Ahlskog, Jonathan Graffradford, Walter A Rocca, Michelle M. MielkeAbstract:Importance To our knowledge, a comprehensive study of the survival and causes of death of persons with synucleinopathies compared with the general population has not been conducted. Understanding the long-term outcomes of these conditions may inform patients and caregivers of the expected disease duration and may help with care planning. Objective To compare survival rates and causes of death among patients with incident, clinically diagnosed synucleinopathies and age- and sex-matched referent participants. Design, Setting, and Participants This population-based study used the Rochester Epidemiology Project medical records–linkage system to identify all residents in Olmsted County, Minnesota, who received a diagnostic code of parkinsonism from 1991 through 2010. A movement-disorders specialist reviewed the medical records of each individual to confirm the presence of parkinsonism and determine the type of Synucleinopathy. For each confirmed patient, an age- and sex-matched Olmsted County resident without parkinsonism was also identified. Main Outcomes and Measures We determined the age- and sex-adjusted risk of death for each type of Synucleinopathy, the median time from diagnosis to death, and the causes of death. Results Of the 461 patients with synucleinopathies, 279 (60.5%) were men, and of the 452 referent participants, 272 (60.2%) were men. From 1991 through 2010, 461 individuals received a diagnosis of a Synucleinopathy (309 [67%] of Parkinson disease, 81 [17.6%] of dementia with Lewy bodies, 55 [11.9%] of Parkinson disease dementia, and 16 [3.5%] of multiple system atrophy with parkinsonism). During follow-up, 68.6% (n = 316) of the patients with synucleinopathies and 48.7% (n = 220) of the referent participants died. Patients with any Synucleinopathy died a median of 2 years earlier than referent participants. Patients with multiple system atrophy with parkinsonism (hazard ratio, 10.51; 95% CI, 2.92-37.82) had the highest risk of death compared with referent participants, followed by those with dementia with Lewy bodies (hazard ratio, 3.94; 95% CI, 2.61-5.94), Parkinson disease with dementia (hazard ratio, 3.86; 95% CI, 2.36-6.30), and Parkinson disease (hazard ratio, 1.75; 95% CI, 1.39-2.21). Neurodegenerative disease was the most frequent cause of death listed on the death certificate for patients, and cardiovascular disease was the most frequent cause of death among referent participants. Conclusions and Relevance Individuals with multiple system atrophy with parkinsonism, dementia with Lewy bodies, and Parkinson disease dementia have increased mortality compared with the general population. The mortality among persons with Parkinson disease is only moderately increased compared with the general population.
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REM Sleep Behavior Disorder in Parkinson's Disease and Other Synucleinopathies
Movement Disorders, 2017Co-Authors: Erik K. St. Louis, Angelica R. Boeve, Bradley F. BoeveAbstract:Rapid eye movement sleep behavior disorder is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. Rapid eye movement sleep behavior disorder may be idiopathic or symptomatic and in both settings is highly associated with Synucleinopathy neurodegeneration, especially Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Rapid eye movement sleep behavior disorder frequently manifests years to decades prior to overt motor, cognitive, or autonomic impairments as the presenting manifestation of Synucleinopathy, along with other subtler prodromal "soft" signs of hyposmia, constipation, and orthostatic hypotension. Between 35% and 91.9% of patients initially diagnosed with idiopathic rapid eye movement sleep behavior disorder at a sleep center later develop a defined neurodegenerative disease. Less is known about the long-term prognosis of community-dwelling younger patients, especially women, and rapid eye movement sleep behavior disorder associated with antidepressant medications. Patients with rapid eye movement sleep behavior disorder are frequently prone to sleep-related injuries and should be treated to prevent injury with either melatonin 3-12 mg or clonazepam 0.5-2.0 mg to limit injury potential. Further evidence-based studies about rapid eye movement sleep behavior disorder are greatly needed, both to enable accurate prognostic prediction of end Synucleinopathy phenotypes for individual patients and to support the application of symptomatic and neuroprotective therapies. Rapid eye movement sleep behavior disorder as a prodromal Synucleinopathy represents a defined time point at which neuroprotective therapies could potentially be applied for the prevention of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. © 2017 International Parkinson and Movement Disorder Society.
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rem sleep behavior disorder updated review of the core features the rem sleep behavior disorder neurodegenerative disease association evolving concepts controversies and future directions
Annals of the New York Academy of Sciences, 2010Co-Authors: Bradley F. BoeveAbstract:Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-Synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving Synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.
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rem sleep behavior disorder updated review of the core features the rbd neurodegenerative disease association evolving concepts controversies and future directions
Annals of the New York Academy of Sciences, 2010Co-Authors: Bradley F. BoeveAbstract:Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. Patients appear to “act out their dreams,” in which the exhibited behaviors mirror the content of the dreams, and the dream content often involves a chasing or attacking theme. The polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straight-forward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-Synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving Synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.
Thierry Baron - One of the best experts on this subject based on the ideXlab platform.
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Investigating the neuroprotective effect of AAV-mediated β-synuclein overexpression in a transgenic model of Synucleinopathy
Scientific Reports, 2018Co-Authors: Dorian Sargent, Jérémy Verchère, Dominique Bétemps, Matthieu Drouyer, Damien Gaillard, Jean-noël Arsac, Latifa Lakhdar, Anna Salvetti, Thierry BaronAbstract:Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases characterized by inclusions mainly composed of α-synuclein (α-syn) aggregates. The objective of this study was to investigate if β-synuclein (β-syn) overexpression could have beneficial effects by inhibiting the aggregation of α-syn. The M83 transgenic mouse is a model of Synucleinopathy, which develops severe motor symptoms associated with aggregation of α-syn. M83 neonate or adult mice were injected with adeno-associated virus vectors carrying the human β-syn gene (AAVβ-syn) or green fluorescent protein gene (AAVGFP) using different injection sites. The M83 disease was - or not - accelerated using extracts of M83 brains injected with brain extract from mouse (M83) or human (MSA) origins. AAV vectors expression was confirmed using Western blot and ELISA technics. AAV mediated β-syn overexpression did not delay the disease onset or reduce the α-syn phosphorylated at serine 129 levels detected by ELISA, regardless of the AAV injection route and the inoculation of brain extracts. Instead, a proteinase-K resistant β-syn staining was detected by immunohistochemistry, specifically in sick M83 mice overexpressing β-syn after inoculation of AAVβ-syn. This study indicated for the first time that viral vector-mediated β-syn overexpression could form aggregates in a model of Synucleinopathy.
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Binding of the PET Radiotracer [18F]BF227 Does not Reflect the Presence of Alpha-Synuclein Aggregates in Transgenic Mice
Current Alzheimer Research, 2014Co-Authors: Elise Levigoureux, Jérémy Verchère, Thierry Baron, Sophie Lancelot, Caroline Bouillot, Fabien Chauveau, Mathieu Verdurand, Thierry Billard, Luc ZimmerAbstract:Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [18F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of Synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [18F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [18F]BF227 PET has no suitable characteristics for monitoring this experimental Synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.
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prion like acceleration of a Synucleinopathy in a transgenic mouse model
Neurobiology of Aging, 2012Co-Authors: Anne-laure Mougenot, Simon Nicot, Anna Bencsik, Eric Morignat, Jérémy Verchère, Latefa Lakhdar, Stéphane Legastelois, Thierry BaronAbstract:Abstract Our aim in this study was to investigate experimentally the possible in vivo transmission of a Synucleinopathy, using a transgenic mouse model (TgM83) expressing the human A53T mutated α-synuclein. Brain homogenates from old TgM83 mice showing motor clinical signs due to the Synucleinopathy and containing insoluble and phosphorylated (pSer129) α-synuclein were intracerebrally inoculated in young TgM83 mice. This triggered an early onset of characteristic motor clinical signs, compared with uninoculated TgM83 mice or to mice inoculated with a brain homogenate from a young, healthy TgM83 mouse. This early disease was associated with insoluble α-synuclein phosphorylated on Ser129, as already identified in old and sick uninoculated TgM83 transgenic mice. Although the molecular mechanisms remain to be determined, acceleration of the pathology following inoculation of mice expressing human mutated α-synuclein with tissues from mice affected by the Synucleinopathy, could be consistent with “prion-like” propagation of the disease.
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Rapid communication Prion-like acceleration of a Synucleinopathy in a transgenic mouse model
2012Co-Authors: Anne-laure Mougenot, Simon Nicot, Anna Bencsik, Eric Morignat, Jérémy Verchère, Latefa Lakhdar, Stéphane Legastelois, Thierry BaronAbstract:Our aim in this study was to investigate experimentally the possible in vivo transmission of a Synucleinopathy, using a transgenic mouse model (TgM83) expressing the human A53T mutated -synuclein. Brain homogenates from old TgM83 mice showing motor clinical signs due to the Synucleinopathy and containing insoluble and phosphorylated (pSer129) -synuclein were intracerebrally inoculated in young TgM83 mice. This triggered an early onset of characteristic motor clinical signs, compared with uninoculated TgM83 mice or to mice inoculated with a brain homogenate from a young, healthy TgM83 mouse. This early disease was associated with insoluble -synuclein phosphorylated on Ser129, as already identified in old and sick uninoculated TgM83 transgenic mice. Although the molecular mechanisms remain to be determined, acceleration of the pathology following inoculation of mice expressing human mutated -synuclein with tissues from mice affected by the Synucleinopathy, could be consistent with “prion-like” propagation of the disease.
Aleksandar Videnovic - One of the best experts on this subject based on the ideXlab platform.
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Idiopathic REM sleep behaviour disorder and neurodegeneration — an update
Nature Reviews Neurology, 2018Co-Authors: Birgit Högl, Ambra Stefani, Aleksandar VidenovicAbstract:Clinically isolated rapid eye movement (REM) sleep behavioural disorder (RBD) is considered to be an early stage of α-Synucleinopathy that can provide a window into the future health of the brain Elementary, minor and major body and limb jerks on surface electromyography (REM sleep without atonia) or video polysomnography are the main hallmarks of RBD Accurate diagnosis of isolated RBD is critical in clinical trials and should be confirmed by polysomnography rather than implied by subjective tools such as questionnaires In patients with isolated RBD, conversion to α-Synucleinopathy often results in Parkinson disease dementia or dementia with Lewy bodies; the highest risk of conversion has been calculated for polysomnography-confirmed isolated RBD The term 'prodromal RBD' should be used (in analogy to prodromal Parkinson disease) to define recognizable precursory disease states before the full diagnostic criteria for isolated RBD are met This prodromal stage might enable the identification of individuals at risk of neurodegeneration even before the development of isolated RBD Idiopathic rapid eye movement (REM) sleep behavioural disorder (RBD) is now recognized as an early marker of α-synucleinopathies. Here, Högl and colleagues review potential biomarkers for RBD and summarize the evidence for a prodromal stage, which might enable disease-modifying intervention. In light of these advances, they reconceptualize idiopathic RBD as isolated RBD. So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-Synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-Synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.
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idiopathic rem sleep behaviour disorder and neurodegeneration an update
Nature Reviews Neurology, 2018Co-Authors: Birgit Högl, Ambra Stefani, Aleksandar VidenovicAbstract:So-called idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), formerly seen as a rare parasomnia, is now recognized as the prodromal stage of an α-Synucleinopathy. Given the very high risk that patients with idiopathic RBD have of developing α-synucleinopathies, such as Parkinson disease (PD), PD dementia, dementia with Lewy bodies or multiple system atrophy, and the outstandingly high specificity and very long interval between the onset of idiopathic RBD and the clinical manifestations of α-synucleinopathies, the prodromal phase of this disorder represents a unique opportunity for potentially disease-modifying intervention. This Review provides an update on classic and novel biomarkers of α-synuclein-related neurodegeneration in patients with idiopathic RBD, focusing on advances in imaging and neurophysiological, cognitive, autonomic, tissue-specific and other biomarkers. We discuss the strengths, potential weaknesses and suitability of these biomarkers for identifying RBD and neurodegeneration, with an emphasis on predicting progression to overt α-Synucleinopathy. The role of video polysomnography in providing quantifiable and potentially treatment-responsive biomarkers of neurodegeneration is highlighted. In light of all these advances, and the now understood role of idiopathic RBD as an early manifestation of α-synuclein disease, we call for idiopathic RBD to be reconceptualized as isolated RBD.
Takeshi Iwatsubo - One of the best experts on this subject based on the ideXlab platform.
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Endoplasmic reticulum stress is important for the manifestations of α-Synucleinopathy in vivo
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Emanuela Colla, Takeshi Iwatsubo, Olga Pletnikova, Juan C. Troncoso, Philippe Coune, Ying Liu, Bernard L. Schneider, Michael K LeeAbstract:Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-Synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-Synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperone in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-Synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53TαS Tg mouse model and the Adeno-associated Virus-transduced rat model of A53T α S-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies.
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Pathological biochemistry of alpha-Synucleinopathy.
Neuropathology : official journal of the Japanese Society of Neuropathology, 2007Co-Authors: Takeshi IwatsuboAbstract:Lewy bodies (LBs) are hallmark lesions in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We raised a monoclonal antibody LB509 against purified LBs from the brains of patients with DLB that strongly immunolabled LBs, and found that alpha-synuclein is one of the major components of LBs. Thus, the deposition of alpha-synuclein, an abundant presynaptic brain protein, as fibrillary aggregates in affected neurons or glial cells, was highlighted as a hallmark lesion of a subset of neurodegenerative disorders, including PD, DLB and multiple system atrophy collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in and multiplication of alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. We then examined the specific posttranslational modifications that characterize and underlie the aggregation of alpha-synuclein in Synucleinopathy brains by mass spectrometry and using a specific antibody, and found that serine 129 of alpha-synuclein deposited in Synucleinopathy lesions is selectively and extensively phosphorylated. Furthermore we generated transgenic C. elegans overexpressing alpha-synuclein in neurons, and found that overexpression of familial PD-linked mutant form of alpha-synuclein impairs functions of dopamine neurons. These findings collectively underscore the importance of deposition of alpha-synuclein as well as its phosphorylation in the pathogenesis of alpha-synucleinopathies.
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analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in lewy body disease
Journal of Neuropathology and Experimental Neurology, 2007Co-Authors: Yuichi Fumimura, Takeshi Iwatsubo, Masako Ikemura, Yuko Saito, Renpei Sengoku, Kazutomi Kanemaru, Motoji Sawabe, Tomio Arai, Masashi Fukayama, Hidehiro MizusawaAbstract:Lewy body disease is defined as Lewy body-related neuronal degeneration involving the nigrostriatal system, limbic-neocortical system, and peripheral autonomic nervous system (PANS). We investigated whether the adrenal gland, which is evolutionarily related to sympathetic ganglia and is routinely examined in general autopsy, could be used to assess pathology of the PANS in Lewy body disease. Brains, spinal cords, and adrenal glands from 783 consecutive autopsy cases from a general geriatric hospital were examined immunohistochemically with antiphosphorylated α-synuclein antibodies and routine staining. Parkinson disease (PD) with dementia and dementia with Lewy bodies (DLB) were defined using 1996 Consensus Guidelines for DLB and the secondary Lewy body-related α-Synucleinopathy or amygdala variants using previously established criteria. Lewy body-related α-Synucleinopathy was found in 207 (26.4%) of 783 cases, with 1 case solely in the adrenal gland. In all 18 PD cases with or without dementia and in 33 of 38 DLB cases, the adrenal gland was involved, but it was spared in all cases of amygdala variants. Our results indicate that the adrenal gland can provide useful information for evaluation of the PANS in Lewy body disease.
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Analysis of alpha-synuclein and its significance
Nihon rinsho. Japanese journal of clinical medicine, 2004Co-Authors: Takashi Nonaka, Takeshi Iwatsubo, Masato HasegawaAbstract:Filamentous alpha-synuclein deposition is the defining hallmark of neurodegenerative synucleinopathies. The onset and progression of these diseases are thought to be related the formation of the alpha-synuclein filaments. We have analyzed posttranslational modifications of the filamentous alpha-synuclein in Synucleinopathy brains by biochemical and protein chemical techniques. Mass spectrometric analysis revealed that deposited alpha-synuclein is highly phosphorylated at Ser129. We also found that alpha-synuclein is ubiquitinated in several Synucleinopathy brains. The ubiquitination sites of soluble and filamentous alpha-synuclein were determined. These data have important implications for understanding the formation of alpha-synuclein filaments in Synucleinopathy brains.
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Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions
The Journal of biological chemistry, 2002Co-Authors: Masato Hasegawa, Takashi Nonaka, Hideo Fujiwara, Koichi Wakabayashi, Hitoshi Takahashi, Virginia M.-y. Lee, John Q. Trojanowski, David J. Mann, Takeshi IwatsuboAbstract:Abstract α-Synuclein is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz disease, which are referred to as α-synucleinopathies. We have shown previously (Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) Nat. Cell Biol. 4, 160–164) that α-synuclein deposited in Synucleinopathy brains is extensively phosphorylated at Ser-129 and migrates at 15 kDa. Here we examined the biochemical characteristics of the additional, higher molecular mass species of phosphorylated α-synuclein-positive polypeptides that also are recovered in the Sarkosyl-insoluble fraction of Synucleinopathy and migrate at about 22 and 29 kDa. These 22 and 29 kDa bands were positive for three different anti-ubiquitin antibodies and comigrated perfectly with in vitro ubiquitinated α-synuclein that may correspond to mono- and diubiquitinated α-synuclein, respectively. Furthermore, cyanogen bromide cleavage of the 22 and 29 kDa polypeptides shifted the mobility to 19 and 26 kDa, respectively, and they retained immunoreactivity for both ubiquitin and α-synuclein. Finally, protein sequence analysis showed that the 19 kDa band contained two amino-terminal sequences of α-synuclein and ubiquitin. These results strongly suggest that phosphorylated α-synuclein is targeted to mono- and diubiquitination in Synucleinopathy brains, which may have implications for mechanisms of these diseases.
Eliezer Masliah - One of the best experts on this subject based on the ideXlab platform.
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oligodendroglial α Synucleinopathy driven neuroinflammation in multiple system atrophy
Brain Pathology, 2019Co-Authors: Alana Hoffmann, Eliezer Masliah, Benjamin Ettle, Kristina Battis, Simone Reiprich, Johannes C M Schlachetzki, Michael Wegner, Tanja Kuhlmann, Markus J RiemenschneiderAbstract:Neuroinflammation and oligodendroglial cytoplasmic α-synuclein (α-syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA-associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α-syncleinopathy. In human putaminal post-mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α-syn inclusions, while gray matter with less α-Synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α-syn under the control of an oligodendrocyte-specific myelin basic protein (MBP) promoter (MBP29-hα-syn mice) was assessed in a pre-symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α-syn load, the corpus callosum and the striatum, of MBP29-hα-syn mice, already at a pre-symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29-hα-syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α-syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α-syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29-hα-syn mice exhibited a similar cellular gene expression profile in white matter regions even pre-symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α-syn inclusions leading to an immune response locally restricted to white matter regions in MSA.
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review novel treatment strategies targeting alpha synuclein in multiple system atrophy as a model of Synucleinopathy
Neuropathology and Applied Neurobiology, 2016Co-Authors: Elvira Valera, Monzio G Compagnoni, Eliezer MasliahAbstract:Neurodegenerative disorders with alpha-synuclein (α-syn) accumulation (synucleinopathies) include Parkinson's disease (PD), PD dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α-syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α-syn is a priority as a disease-modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a Synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α-syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α-syn synthesis, aggregation, clearance, and/or cell-to-cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general Synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery.
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NEDD4-mediated HSF1 degradation underlies α-Synucleinopathy.
Human Molecular Genetics, 2015Co-Authors: Eunhee Kim, Eliezer Masliah, Bin Wang, Namratha Sastry, Peter T. Nelson, Huaibin Cai, Francesca Fang LiaoAbstract:Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin-proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as α-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stress-protective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, whether and how HSF1 is dysregulated during neurodegeneration has not been studied. Here, we discover aberrant HSF1 degradation by aggregated α-synuclein (or α-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via α-synuclein was confirmed by in vivo assessment of mouse and in situ studies of human specimens with α-Synucleinopathy. We demonstrate that elevated NEDD4 is implicated as the responsible ubiquitin E3 ligase for HSF1 degradation through UPS. Furthermore, pharmacologically induced SIRT1-mediated deacetylation can attenuate aberrant NEDD4-mediated HSF1 degradation. Indeed, we define the acetylation status of the Lys 80 residue located in the DNA-binding domain of HSF1 as a critical factor in modulating HSF1 protein stability in addition to its previously identified role in the transcriptional activity. Together with the finding that preserving HSF1 can alleviate α-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying α-Synucleinopathy.
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alpha synuclein is phosphorylated in Synucleinopathy lesions
Nature Cell Biology, 2002Co-Authors: Hideo Fujiwara, Masato Hasegawa, Naoshi Dohmae, Akiko Kawashima, Eliezer Masliah, Matthew S. Goldberg, Jie Shen, Koji Takio, Takeshi IwatsuboAbstract:The deposition of the abundant presynaptic brain protein α-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies1,2. Importantly, the identification of missense mutations in the α-synuclein gene in some pedigrees of familial PD has strongly implicated α-synuclein in the pathogenesis of PD and other synucleinopathies3. However, specific post-translational modifications that underlie the aggregation of α-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of α-synuclein, that this residue is selectively and extensively phosphorylated in Synucleinopathy lesions. Furthermore, phosphorylation of α-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.
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|[alpha]|-Synuclein is phosphorylated in Synucleinopathy lesions
Nature cell biology, 2002Co-Authors: Hideo Fujiwara, Masato Hasegawa, Naoshi Dohmae, Akiko Kawashima, Eliezer Masliah, Matthew S. Goldberg, Jie Shen, Koji Takio, Takeshi IwatsuboAbstract:The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in Synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.
