Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice

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 ubiq...

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Bibliographic Details
Published in:Molecular brain 2022-06, Vol.15 (1), p.54-54, Article 54
Main Authors: Noda, Sachiko, Sato, Shigeto, Fukuda, Takahiro, Ueno, Shinichi, Tada, Norihiro, Hattori, Nobutaka
Format: Article
Language:English
Subjects:
Age
Autophagy
Brain
Cloning
Cullin
Dopamine receptors
Dopaminergic neuron
F-box protein
FBXO7
Genotype & phenotype
Lewy bodies
Micro Report
Mitochondria
Movement disorders
Mutation
Nervous system diseases
Nestin
Neurodegenerative diseases
Neurogenesis
Neurons
p62
Parkinson's disease
Parkinsons disease
Pathology
Proteasomes
Proteolysis
Synuclein
Ubiquitin
Ubiquitin-protein ligase
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Summary: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 : Nestin-Cre) by crossing previously characterized FBXO7 floxed mice (FBXO7 ) with Nestin-Cre mice (Nestin-Cre). The resultant Fbxo7 : 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.
ISSN:1756-6606
1756-6606
DOI:10.1186/s13041-022-00936-5