非表示:
キーワード:
ATP-Dependent Proteases/genetics/*metabolism
Animals
Cell Survival
Humans
Intellectual Disability/genetics/metabolism
Membrane Proteins/genetics/metabolism
Metalloendopeptidases/genetics/metabolism
Mice
Mice, Knockout
Mitochondria/genetics/*metabolism
Mitochondrial Proteins/*biosynthesis/genetics
Muscle Spasticity/genetics/metabolism
Mutation
Nerve Tissue Proteins/genetics/*metabolism
Optic Atrophy/genetics/metabolism
Protein Biosynthesis/*physiology
Purkinje Cells
Spinocerebellar Ataxias/genetics/metabolism
Spinocerebellar Degenerations/genetics/metabolism
要旨:
Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional Afg3l2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of Afg3l2, which revealed a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration.
