Hyejin Hyung, Soyoung Jang, Si-Yong Kim, Ji-Eun Bae, Ji Yeong Park, Su-Geun Lim, Jiwon Ko, Soyeon Jang, Joon Bum Kim, Hee Young Chae, Song Park, Junkoo Yi, Dong Kyu Choi, Myoung Ok Kim, Hyun-Shik Lee, Dong-Hyung Cho, Zae Young Ryoo
{"title":"HSPA9的下调减少了小鼠黑质中酪氨酸羟酶阳性神经元并诱导帕金森病样运动损伤。","authors":"Hyejin Hyung, Soyoung Jang, Si-Yong Kim, Ji-Eun Bae, Ji Yeong Park, Su-Geun Lim, Jiwon Ko, Soyeon Jang, Joon Bum Kim, Hee Young Chae, Song Park, Junkoo Yi, Dong Kyu Choi, Myoung Ok Kim, Hyun-Shik Lee, Dong-Hyung Cho, Zae Young Ryoo","doi":"10.1080/19768354.2025.2569875","DOIUrl":null,"url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (<i>Hspa9</i> <sup>+/-</sup>) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, <i>Hspa9</i> haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in <i>Hspa9</i> <sup>+/-</sup> mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.</p>","PeriodicalId":7804,"journal":{"name":"Animal Cells and Systems","volume":"29 1","pages":"615-627"},"PeriodicalIF":3.2000,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523465/pdf/","citationCount":"0","resultStr":"{\"title\":\"Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.\",\"authors\":\"Hyejin Hyung, Soyoung Jang, Si-Yong Kim, Ji-Eun Bae, Ji Yeong Park, Su-Geun Lim, Jiwon Ko, Soyeon Jang, Joon Bum Kim, Hee Young Chae, Song Park, Junkoo Yi, Dong Kyu Choi, Myoung Ok Kim, Hyun-Shik Lee, Dong-Hyung Cho, Zae Young Ryoo\",\"doi\":\"10.1080/19768354.2025.2569875\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (<i>Hspa9</i> <sup>+/-</sup>) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, <i>Hspa9</i> haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in <i>Hspa9</i> <sup>+/-</sup> mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.</p>\",\"PeriodicalId\":7804,\"journal\":{\"name\":\"Animal Cells and Systems\",\"volume\":\"29 1\",\"pages\":\"615-627\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523465/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Animal Cells and Systems\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/19768354.2025.2569875\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Animal Cells and Systems","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/19768354.2025.2569875","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.
Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9+/-) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9+/- mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.
期刊介绍:
Animal Cells and Systems is the official journal of the Korean Society for Integrative Biology. This international, peer-reviewed journal publishes original papers that cover diverse aspects of biological sciences including Bioinformatics and Systems Biology, Developmental Biology, Evolution and Systematic Biology, Population Biology, & Animal Behaviour, Molecular and Cellular Biology, Neurobiology and Immunology, and Translational Medicine.