1. Dopamine neuron dysfunction and loss in the PrknR275W mouse model of juvenile parkinsonism.
- Author
-
Regoni M, Zanetti L, Sevegnani M, Domenicale C, Magnabosco S, Patel JC, Fernandes MK, Feeley RM, Monzani E, Mini C, Comai S, Cherchi L, De Gregorio D, Soliman I, Ruto F, Croci L, Consalez G, Rodighiero S, Ciammola A, Valtorta F, Morari M, Piccoli G, Rice ME, and Sassone J
- Subjects
- Animals, Mice, Male, Female, Mice, Transgenic, Dopamine metabolism, Substantia Nigra metabolism, Substantia Nigra pathology, Corpus Striatum metabolism, Corpus Striatum pathology, Mice, Inbred C57BL, Gene Knock-In Techniques, Mutation, Missense genetics, Ubiquitin-Protein Ligases genetics, Disease Models, Animal, Dopaminergic Neurons metabolism, Dopaminergic Neurons pathology, Parkinsonian Disorders genetics, Parkinsonian Disorders physiopathology, Parkinsonian Disorders pathology
- Abstract
Mutations in the PRKN gene encoding the protein parkin cause autosomal recessive juvenile parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson's disease mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. To this end, we created a knock-in mouse carrying the homozygous PrknR275W mutation, which is the missense mutation with the highest allelic frequency in PRKN patients. We evaluated the anatomical and functional integrity of the nigrostriatal dopamine (DA) pathway, as well as motor behaviour in PrknR275W mice of both sexes. We report here that PrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that the PrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new Parkinson's disease model in which to study causative mechanisms of the disease and test therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF