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Construct optimization for AAV-mediated human α-syn overexpression, and validation across research settings : Development of a shared tool for the research community

Pardo, Joaquin LU ; Mudannayake, Janitha LU orcid ; Bernal-Conde, Luis Daniel ; Sandoval, Ivette M. ; Dong, Ryan B. ; Avallone, Martino LU ; Marmion, David J. ; Gralen, Addison ; Waite, Lauren LU and Heuer, Andreas LU orcid , et al. (2026) In Journal of Parkinson's Disease 16(5). p.877-894
Abstract

The adeno-associated virus (AAV) alpha-synuclein (α-syn) overexpression model of Parkinson's disease (PD) shares many etiopathological features of the human disease, including the formation of aggregated α-syn, neuroinflammation, and nigral neurodegeneration. However, despite the high face validity of this model, it is notoriously variable, yielding inconsistent results with seemingly similar methodologies. In an effort to streamline the utility of this model for the broader research community, we partnered with The Michael J. Fox Foundation for Parkinson's Research (MJFF) to reduce variability and provide a validated tool to be distributed to the research community. Herein, the intent was to assess numerous vector batches in two... (More)

The adeno-associated virus (AAV) alpha-synuclein (α-syn) overexpression model of Parkinson's disease (PD) shares many etiopathological features of the human disease, including the formation of aggregated α-syn, neuroinflammation, and nigral neurodegeneration. However, despite the high face validity of this model, it is notoriously variable, yielding inconsistent results with seemingly similar methodologies. In an effort to streamline the utility of this model for the broader research community, we partnered with The Michael J. Fox Foundation for Parkinson's Research (MJFF) to reduce variability and provide a validated tool to be distributed to the research community. Herein, the intent was to assess numerous vector batches in two distinct research groups, sharing tissue and cross-analyzing data to ensure rigor and reproducibility of this model. We assessed several variables, including AAV serotype, genome structure, and promoter construct. Our final selection consisted of a self-complementary AAV genome, carrying the hybrid chicken beta-actin promoter, packaged into AAV5. The resultant construct provides for dose-dependent nigrostriatal degeneration and associated indices such as neuroinflammation and behavioral impairments. Moreover, as reported by others, we observed significant toxicity using a reporter fluorophore as a control; instead, we generated and validated a null vector as the accompanying control. These vectors and plasmid genomes are available for distribution via MJFF.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV, alpha-synuclein, animal model, neurodegeneration, substantia nigra, α-syn
in
Journal of Parkinson's Disease
volume
16
issue
5
pages
18 pages
publisher
IOS Press
external identifiers
  • pmid:42185734
  • scopus:105046491920
ISSN
1877-7171
DOI
10.1177/1877718X261447105
language
English
LU publication?
yes
id
63d8ca36-596b-4dd0-9631-53ad19e733d3
date added to LUP
2026-10-06 10:27:55
date last changed
2026-10-06 12:12:50
@article{63d8ca36-596b-4dd0-9631-53ad19e733d3,
  abstract     = {{<p>The adeno-associated virus (AAV) alpha-synuclein (α-syn) overexpression model of Parkinson's disease (PD) shares many etiopathological features of the human disease, including the formation of aggregated α-syn, neuroinflammation, and nigral neurodegeneration. However, despite the high face validity of this model, it is notoriously variable, yielding inconsistent results with seemingly similar methodologies. In an effort to streamline the utility of this model for the broader research community, we partnered with The Michael J. Fox Foundation for Parkinson's Research (MJFF) to reduce variability and provide a validated tool to be distributed to the research community. Herein, the intent was to assess numerous vector batches in two distinct research groups, sharing tissue and cross-analyzing data to ensure rigor and reproducibility of this model. We assessed several variables, including AAV serotype, genome structure, and promoter construct. Our final selection consisted of a self-complementary AAV genome, carrying the hybrid chicken beta-actin promoter, packaged into AAV5. The resultant construct provides for dose-dependent nigrostriatal degeneration and associated indices such as neuroinflammation and behavioral impairments. Moreover, as reported by others, we observed significant toxicity using a reporter fluorophore as a control; instead, we generated and validated a null vector as the accompanying control. These vectors and plasmid genomes are available for distribution via MJFF.</p>}},
  author       = {{Pardo, Joaquin and Mudannayake, Janitha and Bernal-Conde, Luis Daniel and Sandoval, Ivette M. and Dong, Ryan B. and Avallone, Martino and Marmion, David J. and Gralen, Addison and Waite, Lauren and Heuer, Andreas and Davidsson, Marcus and Polinski, Nicole K. and Björklund, Tomas and Manfredsson, Fredric P.}},
  issn         = {{1877-7171}},
  keywords     = {{AAV; alpha-synuclein; animal model; neurodegeneration; substantia nigra; α-syn}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{877--894}},
  publisher    = {{IOS Press}},
  series       = {{Journal of Parkinson's Disease}},
  title        = {{Construct optimization for AAV-mediated human α-syn overexpression, and validation across research settings : Development of a shared tool for the research community}},
  url          = {{http://dx.doi.org/10.1177/1877718X261447105}},
  doi          = {{10.1177/1877718X261447105}},
  volume       = {{16}},
  year         = {{2026}},
}