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Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy : translational implications for interventional therapies

Refolo, Violetta; Bez, Francesco LU ; Polissidis, Alexia; Kuzdas-Wood, Daniela; Sturm, Edith; Kamaratou, Martina; Poewe, Werner; Stefanis, Leonidas; Angela Cenci, M. LU and Romero-Ramos, Marina LU , et al. (2018) In Acta neuropathologica communications 6(1). p.1-24
Abstract

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective... (More)

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.

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keywords
Multiple system atrophy, Neuroinflammation, Striatonigral degeneration, α-synuclein, transgenic mouse
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Acta neuropathologica communications
volume
6
issue
1
pages
1 - 24
publisher
BioMed Central
external identifiers
  • scopus:85049995619
ISSN
2051-5960
DOI
10.1186/s40478-017-0504-y
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English
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yes
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2e359865-0194-4967-a5a6-808b14793093
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2019-06-19 14:33:49
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2019-09-17 04:56:53
@article{2e359865-0194-4967-a5a6-808b14793093,
  abstract     = {<p>Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor         deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In         summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.</p>},
  author       = {Refolo, Violetta and Bez, Francesco and Polissidis, Alexia and Kuzdas-Wood, Daniela and Sturm, Edith and Kamaratou, Martina and Poewe, Werner and Stefanis, Leonidas and Angela Cenci, M. and Romero-Ramos, Marina and Wenning, Gregor K. and Stefanova, Nadia},
  issn         = {2051-5960},
  keyword      = {Multiple system atrophy,Neuroinflammation,Striatonigral degeneration,α-synuclein, transgenic mouse},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {1--24},
  publisher    = {BioMed Central},
  series       = {Acta neuropathologica communications},
  title        = {Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy : translational implications for interventional therapies},
  url          = {http://dx.doi.org/10.1186/s40478-017-0504-y},
  volume       = {6},
  year         = {2018},
}