Animal models of multiple system atrophy

Stefanova, Nadia; Tison, François; Reindl, Markus; Poewe, Werner; Wenning, Gregor K.

doi:10.1016/j.tins.2005.07.002

Cited by 75 publications

(55 citation statements)

References 51 publications

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“…These models are based on overexpression of α-syn in oligodendrocytes and replicate several aspects of MSA pathology (24,25). The PLP-SYN mouse model used in this study displays motor deficits, neuroinflammation, and loss of TH-positive neurons in the SNc in addition to the presence of α-syn inclusions in oligodendrocytes (23,26).…”

Section: Discussionmentioning

confidence: 99%

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Bassil

Fernagut

Bézard

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.alpha-synuclein | multiple system atrophy | caspase-1 | truncation

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Section: Discussionmentioning

confidence: 99%

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Bassil

Fernagut

Bézard

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…En 1969 Graham y Oppenheimer introdujeron el térmi-no AMS, en el que se fueron posteriormente englobando la DEN, la atrofia olivopontocerebelosa (OPCA) y el síndro-me de Shy-Drager como distintos tipos de la misma enfermedad [22][23][24][25][26][27][28][29] . Todos ellos tienen como dato neuropatológico común que les distingue de otras enfermedades neurodegenerativas la presencia de abundantes inclusiones intracitoplasmáticas gliales en el cerebro, descritas en 1989.…”

Section: Degeneración Nigroestriada Y Atrofias Multisistémicas Concepunclassified

Trastornos del movimiento II: otros síndromes parkinsonianos

Jiménez‐Jiménez

Alonso‐Navarro

Piudo³

et al. 2015

Medicine - Programa de Formación Médica Continuada Acreditado

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ResumenEn este artículo se realiza una actualización de los aspectos epidemiológicos, neuropatológicos, neuroquímicos, etiopatogénicos, clínicos, diagnósticos y terapéuticos de los principales síndromes parkinsonianos (con excepción de la enfermedad de Parkinson), incluidos el parkinsonismo inducido por fármacos, el parkinsonismo postencefalítico vascular, la parálisis supranuclear progresiva, las atrofias multisistémicas, la degeneración corticobasal y la enfermedad de cuerpos de Lewy difusos. Abstract Movement disorders (II): other parkinsonian syndromesThis chapter contains an update on the epidemiological, neuropathological, neurochemical, etiopathogenic, clinical, diagnostic and therapeutic aspects of the primary parkinsonian syndromes (with the exception of Parkinson's disease). This includes drug-induced parkinsonism, vascular postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration and diffuse Lewy body disease. Palabras Clave: -Parkinsonismos secundarios -Parkinsonismos-plus -Parálisis supranuclear progresiva -Atrofia multisistémica -Degeneración corticobasal -Enfermedad de cuerpos de Lewy difusos Keywords: -Secondary parkinsonisms -Parkinson's plus -Progressive supranuclear palsy -Multiple system atrophy -Corticobasal degeneration -Diffuse Lewy body disease ACTUALIZACIÓN Parkinsonismo inducido por fármacos Etiología y epidemiologíaAunque el PIF 1-4 se describió inicialmente con los neurolép-ticos clásicos, existen muchos otros fármacos capaces de bloquear los receptores dopaminérgicos o de deplecionar las terminales dopaminérgicas presinápticas que pueden inducir un síndrome parkinsoniano indistinguible de la enfermedad de Parkinson idiopática (EPI) (tabla 1). En nuestro medio, aproximadamente el 25-33% de los casos de parkinsonismos corresponden a PIF. Los fármacos implicados con más frecuencia son los antagonistas del calcio (cinarizina y flunarizina), los neurolépticos antipsicóticos, neurolépticos antivertiginosos (tietilperazina) y las ortopramidas y benzamidas sustituidas. Los neurolépticos atípicos no están exentos de poder causar PIF como efecto secundario, pudiéndose clasificar de menor a mayor riesgo de inducción de PIF en el siguiente orden: risperidona, ziprasidona, olanzapina, quetiapina y clozapina (esto depende de la capacidad de bloqueo de receptores D 2 postsinápticos).Un estudio poblacional en sujetos de 50-89 años de edad en el Tirol italiano mostró unas cifras de prevalencia de PIF del 1,69% (1,15% en varones y 2,14% en mujeres), que

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“…In the recent decade several animal models have been developed to support studies of MSA [173]. Since the etiopathogenesis of the disease remains hitherto largely unknown, the design of MSA animal models has been based on phenotypic replication of main pathological features of the disease which finally result in specific motor dysfunction.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Research in the double toxin-double lesion rat model has evidenced the possibility of ''turning MSA into PD'' phenotype and recovering dopaminergic responsiveness by striatal allografting [85,173,201]. Current studies target the role of GCI-pathology on graft survival and functional activity [176].…”

Section: Neuroprotectionmentioning

confidence: 99%

Recent developments in multiple system atrophy

Wenning

Stefanova

2009

J Neurol

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Multiple system atrophy (MSA) is a rare late onset neurodegenerative disorder which presents with autonomic failure and a complicated motor syndrome including atypical parkinsonism, ataxia and pyramidal signs. MSA is a glial alpha-synucleinopathy with rapid progression and currently poor therapeutic management. This paper reviews the clinical features, natural history and novel diagnostic criteria for MSA as well as contemporary knowledge on pathogenesis based on evidence from neuropathological studies and experimental models. An outline of the rationale for managing symptomatic deterioration in MSA is provided together with a summary of novel experimental therapeutic approaches to decrease disease progression.

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Animal models of multiple system atrophy

Cited by 75 publications

References 51 publications

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Trastornos del movimiento II: otros síndromes parkinsonianos

Recent developments in multiple system atrophy

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