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Mol. Neurodegener., Feb 28 2025, 20 (1) | https://doi.org/10.1186/s13024-025-00814-3
Preclinical studies and transcriptome analysis in a model of Parkinson's disease with dopaminergic ZNF746 expression
Ji Hun Kim1†, Sumin Yang2†, Hyojung Kim1†, Dang‑Khoa Vo3, Han‑Joo Maeng3, Areum Jo1, Joo‑Heon Shin4, Joo‑Ho Shin1, Hyeon‑Man Baek5, Gum Hwa Lee6, Sung‑Hyun Kim2, Key‑Hwan Lim7, Valina L. Dawson8,9,10,11, Ted M. Dawson8,10,11,12, Jae‑Yeol Joo2* and Yunjong Lee1*
1Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute (SBRI), Suwon 16419, Republic of Korea.
2Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea.
3College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
4Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
5Department of Health Sciences & Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea.
6College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
7Department of Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju‑Si 28160, Republic of Korea.
8Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
†Ji Hun Kim, Sumin Yang and Hyojung Kim contributed equally to this work.
*Correspondence: Jae‑Yeol Joo, Yunjong Lee
1Department of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute (SBRI), Suwon 16419, Republic of Korea.
2Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea.
3College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.
4Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
5Department of Health Sciences & Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea.
6College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
7Department of Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju‑Si 28160, Republic of Korea.
8Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
†Ji Hun Kim, Sumin Yang and Hyojung Kim contributed equally to this work.
*Correspondence: Jae‑Yeol Joo, Yunjong Lee
Abstract
Background: The parkin-interacting substrate (PARIS, also known as ZNF746) is a transcriptional repressor, whose accumulation and phosphorylation play central pathological roles in Parkinson's disease (PD). PARIS-induced transcriptional repression of PGC-1α or MDM4 contributes to mitochondrial dysfunction and p53-dependent neuron loss in PD. Despite the important role of PARIS in PD pathogenesis, unbiased transcriptomic profiles influenced by PARIS accumulation in dopaminergic neurons remain unexplored.
Methods: We engineered Tet-Off conditional transgenic mice expressing PARIS in dopaminergic neurons, driven by DAT-PF-tTA driver mice. The conditional PARIS transgenic mice were characterized by PD-associated pathologies, including progressive dopamine cell loss, neuroinflammation, PGC-1α repression, and mitochondrial proteome alteration. Motor impairment was assessed using pole and rotarod tests. L-DOPA and c-Abl inhibitors were administered to PARIS transgenic mice to evaluate their therapeutic efficacy. The transcriptomic profiles and gene ontology clusters were analyzed by bulk and single-nucleus RNA-seq for the ventral midbrains from PARIS transgenic and age-matched controls.
Results: Conditional dopaminergic PARIS expression in mice led to the robust and selective dopaminergic neuron degeneration, neuroinflammation, and striatal dopamine deficits, resulting in L-DOPA-responsive motor impairments. Consistent with the results of previous reports, PARIS suppressed dopaminergic PGC-1α expression, disturbed mitochondrial marker protein expression, and reduced COXIV-labeled mitochondria in dopamine neurons. Pharmacological inhibition of c-Abl activity in PARIS transgenic mice largely prevents PD-associated pathological features. Unbiased transcriptomic analysis revealed PARIS-regulated differentially expressed genes (DEGs), both collectively and in a cell-type-specific manner, along with enriched biological pathways linked to PD pathogenesis. Single-cell resolution transcriptomic analysis confirmed repression of PGC-1α and several mitochondria-related target genes in dopaminergic cells. Additionally, we identified distinct glial cell subpopulations and DEGs associated with PD pathogenesis.
Conclusions: Conditional PARIS transgenic mice recapitulate robust and dopaminergic neuron-selective pathological features of PD, allowing the preclinical evaluation of antisymptomatic and disease-modifying therapeutic strategies within a couple of months. Based on this new PD mouse model, we provide unbiased bulk and single-nucleus transcriptomic profiles that are regulated by PARIS and potentially contribute to PD pathogenesis. A PD mouse model with flexible pathology induction capacity and a whole transcriptome could serve as a useful resource for translational PD research.
Methods: We engineered Tet-Off conditional transgenic mice expressing PARIS in dopaminergic neurons, driven by DAT-PF-tTA driver mice. The conditional PARIS transgenic mice were characterized by PD-associated pathologies, including progressive dopamine cell loss, neuroinflammation, PGC-1α repression, and mitochondrial proteome alteration. Motor impairment was assessed using pole and rotarod tests. L-DOPA and c-Abl inhibitors were administered to PARIS transgenic mice to evaluate their therapeutic efficacy. The transcriptomic profiles and gene ontology clusters were analyzed by bulk and single-nucleus RNA-seq for the ventral midbrains from PARIS transgenic and age-matched controls.
Results: Conditional dopaminergic PARIS expression in mice led to the robust and selective dopaminergic neuron degeneration, neuroinflammation, and striatal dopamine deficits, resulting in L-DOPA-responsive motor impairments. Consistent with the results of previous reports, PARIS suppressed dopaminergic PGC-1α expression, disturbed mitochondrial marker protein expression, and reduced COXIV-labeled mitochondria in dopamine neurons. Pharmacological inhibition of c-Abl activity in PARIS transgenic mice largely prevents PD-associated pathological features. Unbiased transcriptomic analysis revealed PARIS-regulated differentially expressed genes (DEGs), both collectively and in a cell-type-specific manner, along with enriched biological pathways linked to PD pathogenesis. Single-cell resolution transcriptomic analysis confirmed repression of PGC-1α and several mitochondria-related target genes in dopaminergic cells. Additionally, we identified distinct glial cell subpopulations and DEGs associated with PD pathogenesis.
Conclusions: Conditional PARIS transgenic mice recapitulate robust and dopaminergic neuron-selective pathological features of PD, allowing the preclinical evaluation of antisymptomatic and disease-modifying therapeutic strategies within a couple of months. Based on this new PD mouse model, we provide unbiased bulk and single-nucleus transcriptomic profiles that are regulated by PARIS and potentially contribute to PD pathogenesis. A PD mouse model with flexible pathology induction capacity and a whole transcriptome could serve as a useful resource for translational PD research.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-03-04)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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