The vulnerability of nigral dopamine neurons to mitochondrial complex I deletion in the adult mouse: implications for Parkinson's disease pathogenesis

Abstract

Parkinson's disease (PD) is a neurodegenerative movement disorder, characterized by the motor symptoms of tremor, rigidity, postural instability and slowness of movement. These motor symptoms are caused by the death of the dopamine-producing neurons in the substantia nigra (SN) of the midbrain, however the underlying cause of this selective neurodegeneration is unknown. Many lines of evidence support a causative role for mitochondria in this dopaminergic cell death, and specifically the inhibition of complex I of the electron transport chain. Here we show that the specific removal of complex I function from the mouse does not produce a Parkinsonian loss of dopaminergic cell bodies, nor a loss of the dopamine-producing protein tyrosine hydroxylase (TH) in the striatum. However, we did observe severe axonal dystrophy in dopaminergic axons, and a reduction of mitochondrial size consistent with decreased mitochondrial fusion, both of which are implicated in PD pathogenesis. These data suggest that the inhibition of complex I is not sufficient to account for the selective dopaminergic cell death of PD, but that it is consistent with a cooperative role in the degeneration of the nigrostriatal pathway and the loss of dopaminergic axons.