BACKGROUND/AIMS: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. METHODS: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN(-/-)) and measured the behavioral and histopathological features of PD. RESULTS: Aged (15-to 20-month-old) TN(-/-) mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. CONCLUSION: The TN(-/-) mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.
BACKGROUND/AIMS: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. METHODS: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN(-/-)) and measured the behavioral and histopathological features of PD. RESULTS: Aged (15-to 20-month-old) TN(-/-) mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. CONCLUSION: The TN(-/-) mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.
Authors: Ana Kolicheski; Ronald L Walton; Alexandra I Soto-Beasley; Michael G Heckman; Ryan J Uitti; Francine Parfitt; Michelle R Graff-Radford; Zbigniew K Wszolek; Neill R Graff-Radford; Owen A Ross Journal: J Gerontol A Biol Sci Med Sci Date: 2020-09-16 Impact factor: 6.053
Authors: Anthony L Gaeta; J Brucker Nourse; Karolina Willicott; Luke E McKay; Candice M Keogh; Kylie Peter; Shannon N Russell; Shusei Hamamichi; Laura A Berkowitz; Kim A Caldwell; Guy A Caldwell Journal: PLoS Genet Date: 2022-08-19 Impact factor: 6.020
Authors: Kenneth McDonald; Nadezhda Glezeva; John Baugh; Chris J Watson; Patrick Collier; James O'Reilly; Eoin O'Connell; Isaac Tea; Adam Russell-Hallinan; Claire Tonry; Steve Pennington; Joe Gallagher; Mark Ledwidge Journal: Sci Rep Date: 2020-05-05 Impact factor: 4.379