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Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks

Marciano, Sabina ; Ionescu, Tudor M. ; Saw, Ran Sing ; Cheong, Rachel Y. LU ; Kirik, Deniz LU ; Maurer, Andreas ; Pichler, Bernd J. and Herfert, Kristina (2022) In Proceedings of the National Academy of Sciences of the United States of America 119(40).
Abstract

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target... (More)

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9–mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CRISPR-Cas9, dopamine, PET, resting-state functional MRI, VMAT2
in
Proceedings of the National Academy of Sciences of the United States of America
volume
119
issue
40
article number
e2122552119
publisher
National Academy of Sciences
external identifiers
  • scopus:85139446111
  • pmid:36161926
ISSN
0027-8424
DOI
10.1073/pnas.2122552119
language
English
LU publication?
yes
id
66eeaed9-0ac9-44f3-a57c-59063c6eb143
date added to LUP
2022-12-19 10:21:12
date last changed
2024-06-13 23:40:57
@article{66eeaed9-0ac9-44f3-a57c-59063c6eb143,
  abstract     = {{<p>Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9–mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.</p>}},
  author       = {{Marciano, Sabina and Ionescu, Tudor M. and Saw, Ran Sing and Cheong, Rachel Y. and Kirik, Deniz and Maurer, Andreas and Pichler, Bernd J. and Herfert, Kristina}},
  issn         = {{0027-8424}},
  keywords     = {{CRISPR-Cas9; dopamine; PET; resting-state functional MRI; VMAT2}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{40}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks}},
  url          = {{http://dx.doi.org/10.1073/pnas.2122552119}},
  doi          = {{10.1073/pnas.2122552119}},
  volume       = {{119}},
  year         = {{2022}},
}