Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy

Elena Espa, Erik K.H. Clemensson, Kelvin C. Luk, Andreas Heuer, Tomas Björklund, M. Angela Cenci

Research output: Contribution to journalArticlepeer-review


Background: Cortical α-synuclein pathology plays a role in the development of cognitive dysfunction in both Parkinson's disease and dementia with Lewy bodies, although the causative cellular lesions have remained unclear. We aimed to address causal links between α-synuclein-driven pathology in the cerebral cortex and the development of cognitive impairments using new experimental models. Methods: Neuronal overexpression of human α-synuclein was induced in the rat medial prefrontal cortex using viral vectors. This was combined with inoculations of preformed fibrils of human α-synuclein in some animals. Rats were evaluated with tests probing prefrontal cognitive functions (delayed matching/nonmatching to position and 5-choice serial reaction time task). Patterns of neuropathology were characterized immunohistochemically. Results: Neither α-synuclein overexpression nor the fibril seeds alone yielded any behavioral phenotype. In contrast, combining the 2 approaches produced significant impairments in working memory, attention, and inhibitory control. All animals injected with α-synuclein vectors exhibited high immunoreactivity for human α-synuclein in the medial prefrontal cortex and its primary projection targets. However, only when this overexpression was combined with fibril inoculations did animals exhibit large, proteinase K-resistant and Ser129-phosphorylated α-synuclein intraneuronal inclusions in the medial prefrontal cortex and its closely interconnected brain regions. The inclusions were associated with distorted dendritic morphologies and partial neuronal loss in the targeted cortical areas. Conclusions: Cortical overexpression of human α-synuclein is not sufficient to produce cognitive dysfunction, whereas combining this overexpression with fibril seeds yields both cognitive and histopathological phenotypes that are relevant to human Lewy body disease.

Original languageEnglish
Pages (from-to)1699-1710
JournalMovement Disorders
Issue number11
Early online date2019 Aug 26
Publication statusPublished - 2019

Subject classification (UKÄ)

  • Neurosciences

Free keywords

  • dopamine neurons
  • genetic models
  • nonmotor symptoms
  • prion-like propagation


Dive into the research topics of 'Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy'. Together they form a unique fingerprint.

Cite this