Loss of One Engrailed1 Allele Enhances Induced α -Synucleinopathy

Diptaman Chatterjee, Daniel Saiz Sanchez, Emmanuel Quansah, Nolwen L. Rey, Sonia George, Katelyn Becker, Zachary Madaj, Jennifer A. Steiner, Jiyan Ma, Martha L.Escobar Galvis, Jeffrey H. Kordower, Patrik Brundin

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: Parkinson's disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α-synuclein (α-syn) pre-formed fibril (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1 + /-) mouse that features several pathophysiological hallmarks of clinical PD. Objective: To test the hypothesis that the neuropathological changes in the En1 + /- mice will promote formation of α-syn aggregates following intrastriatal injections of pathogenic human α-syn PFFs. Methods: We unilaterally injected PFFs into the striata of 1-month-old En1 + /- and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. Results: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1 + /- mice exhibited a near-threefold increase in pS129-α-syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1 + /- mice also displayed significant increases in pS129-α-syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129-α-syn-positive aggregation in En1 + /- mice in multiple cortical regions. Conclusions: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological α-syn, potentially due to En1-loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could result in a PD mouse model that predicts which experimental therapies will be effective in PD.

Original languageEnglish (US)
Pages (from-to)315-326
Number of pages12
JournalJournal of Parkinson's Disease
Issue number2
StatePublished - 2019
Externally publishedYes


  • Parkinson's disease
  • engrailed
  • misfolded proteins
  • mouse models
  • neurodegeneration
  • propagation
  • proteinopathy
  • α -Synuclein

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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