Work

Dopaminergic Neuron‐Specific Tfam Knockout Links Inter‐Organelle Miscommunication to Early‐Onset Parkinsonism

Year: 2025

Type: article

Abstract: ABSTRACT Parkinson's disease (PD) is characterized by mitochondrial dysfunction and dopaminergic neuron loss, with multiple subtypes existing due to various clinical manifestations. Compared to sporadic PD, early‐onset PD is underrepresented due to its idiopathic or familial nature. How mitochondrial instability drives early‐onset PD‐associated neurodegeneration requires further clarification. Here, we used a dopaminergic neuron‐specific Tfam conditional knockout (cKO) mouse model to investigate how mitochondrial transcription factor A (TFAM) deficiency impacts early‐onset PD pathogenesis. As early as 2 months old, Tfam cKO mice exhibited progressive motor deficits, α‐synuclein accumulation, and TH + neuronal loss in the substantia nigra pars compacta (SNpc), culminating in significantly reduced body weight and shortened lifespan. Several hallmarks of mitochondrial dysfunction were observed in Tfam cKO neurons, including mtDNA depletion and impaired respiration, lowered NAD + /NADH ratio and membrane potential, accompanied by elevated pSer65 ubiquitin and ER stress activation. Transcriptomic profiling revealed dysregulated inter‐organelle communication, with downregulated nicotinic acetylcholine receptor (nAChR) subunits and compensatory nuclear ribosomal gene upregulation in Tfam cKO neurons. Pharmacological mitophagy inhibition worsened dopaminergic neuron loss in Tfam cKO mice, partially due to cytosolic mtDNA leakage activating the cGAS‐cGAMP‐TBK1 inflammatory axis, exacerbating neuroinflammation and neuronal death. Genetic cGAS ablation attenuated neuroinflammation and delayed behavioral decline but failed to rescue mitochondrial defects or survival. In conclusion, our findings suggest Tfam cKO mice as a model linking inter‐organelle miscommunication to early‐onset PD pathogenesis. Targeted knockout of cGAS attenuates neuroinflammation in Tfam cKO mice, but not the overall PD symptoms and lifespan.

Source: The FASEB Journal

DOI: 10.1096/fj.202501454rr

Authors: Weiyan Shen, Mengling Zheng, Yanlin Zhao, Feitao Ni, Xudong Zhu

Institutions: Jinan University, Hangzhou Normal University, Shantou University Medical College, Shenzhen Third People’s Hospital

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze