Professor Yunjong Lee’s research team (first authors: Ji Hun Kim, Ph.D. student; Hyo Jung Kim, Ph.D.; and Prof. Yunjong Lee) at the Department of Pharmacology, Sungkyunkwan University School of Medicine, has developed a conditional Tet-off transgenic mouse model expressing ZNF746 (PARIS) specifically in midbrain dopaminergic neurons to elucidate the molecular pathogenesis of Parkinson’s disease (PD) and to enable preclinical evaluation of therapeutic agents.

PARIS (ZNF746) is a substrate of the autosomal recessive PD gene Parkin and is known as a transcriptional repressor that accumulates in the brains of PD patients, playing a direct pathogenic role in dopaminergic neuronal degeneration.

PARIS represses key regulators of cellular survival, including PGC-1α, a master regulator of mitochondrial biogenesis, and MDM4, an upstream modulator of the apoptosis regulator p53, thereby leading to metabolic dysfunction and neuronal death.

This study was conducted in collaboration with Professor Jaeyoul Joo’s research group (co-first authors: Prof. Jaeyoul Joo and Soomin Yang) at the College of Pharmacy, Hanyang University, who performed single-nuclear transcriptome analysis to systematically characterize cell-type-specific pathological alterations.

A major challenge in PD research has been the lack of an animal model that faithfully reproduces the progressive and relatively selective degeneration of dopaminergic neurons, the hallmark pathology of the disease.

To overcome this limitation, Prof. Lee’s team established a Tet-off genetic switch–based model that enables adult-onset, dopaminergic neuron–specific expression of PARIS, avoiding developmental lethality caused by early transgene expression.

This model successfully recapitulates progressive motor deficits, clinically relevant extent of dopaminergic neuronal loss, mitochondrial dysfunction, and neuroinflammatory activation over a two-month period, overcoming key limitations of previous transgenic PD models.

Using this model, the team further conducted preclinical drug validation studies, demonstrating that L-DOPA, a symptomatic dopamine replacement therapy, ameliorates motor deficits, while the c-Abl inhibitor Nilotinib suppresses neurodegeneration and neuroinflammation, thereby exerting disease-modifying effects.

These results establish this model as a robust preclinical platform for evaluating both symptomatic and disease-modifying therapeutic candidates for PD.

In addition, by combining single-nuclear transcriptomic and protein-level analyses of the midbrain region, the study identified the c-Abl–PARIS signaling axis as a key pathogenic pathway that suppresses PGC-1α–mediated mitochondrial biogenesis, activates p53-dependent apoptotic signaling, and promotes glial inflammatory remodeling.

Collectively, this research presents a novel PARIS-expressing PD mouse model that overcomes the limited pathological fidelity of conventional transgenic systems, providing a powerful experimental platform for elucidating molecular pathomechanisms and assessing preclinical efficacy of therapeutic candidates targeting neurodegeneration and inflammation in Parkinson’s disease.

※ Title: Preclinical studies and transcriptome analysis in a model of Parkinson’s disease with dopaminergic ZNF746 expression
※ Journal: Molecular Neurodegeneration
※ Paper Link: https://doi.org/10.1186/s13024-025-00814-3
※ Portal(Pure): https://pure.skku.edu/en/persons/yunjong-lee/