Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice
Sachiko Noda, Shigeto Sato, Takahiro Fukuda, Shin‐Ichi Ueno, Norihiro Tada, Nobutaka Hattori
Abstract
Abstract Parkinson’s disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7) (PARK15) mutations cause early-onset Parkinson’s disease. FBXO7 is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its neuronal relevance and function have not been elucidated. To determine its function in neurons, we generated neuronal cell-specific FBXO7 conditional knockout mice (FBXO7 flox/flox : Nestin-Cre) by crossing previously characterized FBXO7 floxed mice (FBXO7 flox/flox ) with Nestin-Cre mice (Nestin-Cre). The resultant Fbxo7 flox/flox : Nestin-Cre mice showed juvenile motor dysfunction, including hindlimb defects and decreased numbers of dopaminergic neurons. Fragmented mitochondria were observed in dopaminergic and cortical neurons. Furthermore, p62- and synuclein-positive Lewy body-like aggregates were identified in neurons. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system that includes the ubiquitin–proteasome system, in controlling intracellular inclusion body formation. These data indicate that the pathologic processes associated with the proteolytic and mitochondrial degradation systems play a crucial role in the pathogenesis of PD.