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Intra-striatal infusion of the small molecule alpha-synuclein aggregator, FN075, fails to enhance Parkinsonism in a subclinical AAV-alpha-synuclein rat model.
  • +7
  • Tommy Patton,
  • Giulia Comini,
  • Kaushik Narasimhan,
  • Andrew Cairns,
  • Jörgen Ådén,
  • Fredrik Almqvist,
  • Alexis Bemelmans,
  • Emmanuel Brouillet,
  • Declan McKernan,
  • Eilis Dowd
Tommy Patton
University of Galway
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Giulia Comini
University of Galway
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Kaushik Narasimhan
University of Galway
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Andrew Cairns
Umeå University
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Jörgen Ådén
Umeå University
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Fredrik Almqvist
Umeå University
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Alexis Bemelmans
Paris-Saclay University
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Emmanuel Brouillet
Paris-Saclay University
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Declan McKernan
University of Galway

Corresponding Author:declan.mckernan@universityofgalway.ie

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Eilis Dowd
National University of Ireland Galway
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Abstract

Numerous challenges hinder the development of neuroprotective treatments for Parkinson’s disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α-synuclein is widely considered the most relevant model, however this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α-synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of AAV-α-synuclein and FN075 into the rat brain can replicate α-synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson’s disease. Rats received a unilateral injection of AAV-α-synuclein (or AAV-GFP) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post-mortem. As anticipated, AAV-α-synuclein led to extensive overexpression of human α-synuclein throughout the nigrostriatal pathway, as well as elevated levels of pathological and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α-synuclein pathology. Furthermore, despite the extensive α-synuclein pathology, neither administration of AAV-α-synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson’s disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson’s disease.
Submitted to European Journal of Neuroscience
09 Feb 2024Reviewer(s) Assigned
19 Mar 2024Editorial Decision: Revise Major
27 May 20241st Revision Received
28 May 2024Reviewer(s) Assigned
26 Jun 2024Editorial Decision: Revise Minor
28 Jun 20242nd Revision Received
29 Jun 2024Assigned to Editor
29 Jun 2024Submission Checks Completed
29 Jun 2024Review(s) Completed, Editorial Evaluation Pending
29 Jun 2024Reviewer(s) Assigned
13 Jul 2024Editorial Decision: Revise Major
19 Jul 20243rd Revision Received
21 Jul 2024Review(s) Completed, Editorial Evaluation Pending
21 Jul 2024Submission Checks Completed
21 Jul 2024Assigned to Editor
21 Jul 2024Editorial Decision: Accept