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Compared to sporadic PD, early\u2010onset PD is underrepresented due to its idiopathic or familial nature. How mitochondrial instability drives early\u2010onset PD\u2010associated neurodegeneration requires further clarification. Here, we used a dopaminergic neuron\u2010specific\n                    <jats:italic>Tfam<\/jats:italic>\n                    conditional knockout (cKO) mouse model to investigate how mitochondrial transcription factor A (TFAM) deficiency impacts early\u2010onset PD pathogenesis. As early as 2 months old,\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO mice exhibited progressive motor deficits, \u03b1\u2010synuclein accumulation, and TH\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO neurons, including mtDNA depletion and impaired respiration, lowered NAD\n                    <jats:sup>+<\/jats:sup>\n                    \/NADH ratio and membrane potential, accompanied by elevated pSer65 ubiquitin and ER stress activation. Transcriptomic profiling revealed dysregulated inter\u2010organelle communication, with downregulated nicotinic acetylcholine receptor (nAChR) subunits and compensatory nuclear ribosomal gene upregulation in\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO neurons. Pharmacological mitophagy inhibition worsened dopaminergic neuron loss in\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO mice, partially due to cytosolic mtDNA leakage activating the cGAS\u2010cGAMP\u2010TBK1 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\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO mice as a model linking inter\u2010organelle miscommunication to early\u2010onset PD pathogenesis. Targeted knockout of cGAS attenuates neuroinflammation in\n                    <jats:italic>Tfam<\/jats:italic>\n                    cKO mice, but not the overall PD symptoms and lifespan.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501454rr","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T16:05:39Z","timestamp":1754669139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dopaminergic Neuron\u2010Specific\n                    <i>Tfam<\/i>\n                    Knockout Links Inter\u2010Organelle Miscommunication to Early\u2010Onset Parkinsonism"],"prefix":"10.1096","volume":"39","author":[{"given":"Weiyan","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Zhejiang Key Laboratory of Medical Epigenetics Hangzhou Normal University  Hangzhou China"},{"name":"Center for Translational Medicine, the Third People's Hospital of Longgang District &amp; Longgang Institute of Medical Imaging Shantou University Medical College  Shenzhen China"},{"name":"Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengling","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Zhejiang Key Laboratory of Medical Epigenetics Hangzhou Normal University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Zhejiang Key Laboratory of Medical Epigenetics Hangzhou Normal University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feitao","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Zhejiang Key Laboratory of Medical Epigenetics Hangzhou Normal University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-6800","authenticated-orcid":false,"given":"Xudong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Zhejiang Key Laboratory of Medical Epigenetics Hangzhou Normal University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61393-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00218-X"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1808-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.22360"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.08.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.06.031"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaf051"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2015.10.021"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24571"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-022-00456-x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101817"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01513-9"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12989"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04059-0"},{"key":"e_1_2_9_17_1","article-title":"Limitations of Animal Models of Parkinson's Disease","volume":"2011","author":"Potashkin J. 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