The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related t...

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Autores principales:	Rachel Kelly, Andrew G. Cairns, Jörgen Ådén, Fredrik Almqvist, Alexis-Pierre Bemelmans, Emmanuel Brouillet, Tommy Patton, Declan P. McKernan, Eilís Dowd
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Parkinson’s alpha-synuclein adeno-associated virus AAV phospho-alpha-synuclein Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c447a4e33b7344ddb7f816064af2a6e0
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spelling	oai:doaj.org-article:c447a4e33b7344ddb7f816064af2a6e02021-11-25T16:53:49ZThe Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models10.3390/biom111116852218-273Xhttps://doaj.org/article/c447a4e33b7344ddb7f816064af2a6e02021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1685https://doaj.org/toc/2218-273XAnimal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.Rachel KellyAndrew G. CairnsJörgen ÅdénFredrik AlmqvistAlexis-Pierre BemelmansEmmanuel BrouilletTommy PattonDeclan P. McKernanEilís DowdMDPI AGarticleParkinson’salpha-synucleinadeno-associated virusAAVphospho-alpha-synucleinMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1685, p 1685 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson’s alpha-synuclein adeno-associated virus AAV phospho-alpha-synuclein Microbiology QR1-502
spellingShingle	Parkinson’s alpha-synuclein adeno-associated virus AAV phospho-alpha-synuclein Microbiology QR1-502 Rachel Kelly Andrew G. Cairns Jörgen Ådén Fredrik Almqvist Alexis-Pierre Bemelmans Emmanuel Brouillet Tommy Patton Declan P. McKernan Eilís Dowd The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
description	Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.
format	article
author	Rachel Kelly Andrew G. Cairns Jörgen Ådén Fredrik Almqvist Alexis-Pierre Bemelmans Emmanuel Brouillet Tommy Patton Declan P. McKernan Eilís Dowd
author_facet	Rachel Kelly Andrew G. Cairns Jörgen Ådén Fredrik Almqvist Alexis-Pierre Bemelmans Emmanuel Brouillet Tommy Patton Declan P. McKernan Eilís Dowd
author_sort	Rachel Kelly
title	The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
title_short	The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
title_full	The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
title_fullStr	The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
title_full_unstemmed	The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models
title_sort	small molecule alpha-synuclein aggregator, fn075, enhances alpha-synuclein pathology in subclinical aav rat models
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c447a4e33b7344ddb7f816064af2a6e0
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The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

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