Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein

Mariangela Massaro Cenere; Marta Tiberi; Emanuela Paldino; Sebastian Luca D'Addario; Mauro Federici; Cecilia Giacomet; Debora Cutuli; Alessandro Matteocci; Francesca Cossa; Beatrice Zarrilli; Nicolas Casadei; Ada Ledonne; Laura Petrosini; Nicola Berretta; Francesca Romana Fusco; Valerio Chiurchiù; Nicola B Mercuri

doi:10.1038/s41531-024-00824-w

Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein

NPJ Parkinsons Dis. 2024 Nov 5;10(1):213. doi: 10.1038/s41531-024-00824-w.

Authors

Mariangela Massaro Cenere^{1

2

3}, Marta Tiberi^{4

5}, Emanuela Paldino⁶, Sebastian Luca D'Addario^{7

8}, Mauro Federici⁷, Cecilia Giacomet^{7

4

8}, Debora Cutuli^{7

9}, Alessandro Matteocci^{5

10}, Francesca Cossa^{7

4

8}, Beatrice Zarrilli^{7

4

8}, Nicolas Casadei¹¹, Ada Ledonne^{7

4

8}, Laura Petrosini⁷, Nicola Berretta^{7

8}, Francesca Romana Fusco⁶, Valerio Chiurchiù^#^{5

12}, Nicola B Mercuri^#^{13

14

15}

Affiliations

¹ Department of Experimental Neuroscience, Santa Lucia Foundation IRCCS, Rome, Italy. [email protected].
² Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. [email protected].
³ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected].
⁴ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁵ Laboratory of Resolution of Neuroinflammation, Santa Lucia Foundation IRCCS, Rome, Italy.
⁶ Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS, Rome, Italy.
⁷ Department of Experimental Neuroscience, Santa Lucia Foundation IRCCS, Rome, Italy.
⁸ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁹ Department of Psychology, Sapienza University of Rome, Rome, Italy.
¹⁰ PhD program in Immunology, Molecular Medicine and Applied biotechnologies, University of Rome Tor Vergata, 00133, Rome, Italy.
¹¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹² Institute of Translational Pharmacology, National Research Council, Rome, Italy.
¹³ Department of Experimental Neuroscience, Santa Lucia Foundation IRCCS, Rome, Italy. [email protected].
¹⁴ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. [email protected].
¹⁵ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [email protected].

^# Contributed equally.

Abstract

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca^+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca^+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca^+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.