Journal
MOLECULAR BRAIN
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13041-022-00936-5
Keywords
Parkinson's disease; FBXO7; Dopaminergic neuron; Mitochondria; Synuclein; p62
Categories
Funding
- JSPS [19K07850]
- Grants-in-Aid for Scientific Research [19K07850] Funding Source: KAKEN
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The study investigated the role of FBXO7 gene mutations in Parkinson's disease and found that these mutations lead to a decrease in dopaminergic neurons and the formation of protein aggregates. They also discovered mitochondrial fragmentation in neuronal cells, suggesting that dysfunction in proteolytic and mitochondrial degradation systems plays a crucial role in the development of Parkinson's disease.
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.
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