Abstract
DJ-1 is a multifunctional protein affecting different biological and cellular processes. In addition, DJ-1 has roles in regulating mitochondrial function. Loss-of-function mutations in DJ-1 were found to cause an autosomal recessive form of Parkinson’s disease. One of the main pathological features of PD is loss of dopamine neurons in the nigrostriatal pathway. DJ-1 knockout (KO) rats exhibit progressive nigral neurodegeneration with about 50% dopaminergic cell loss at 8 months of age. In order to assess the effects of DJ-1 deficiency on neuronal mitochondria prior to neuron loss, we performed proteomic analysis of synaptic mitochondria isolated from the striatum, the location of nigrostriatal pathway nerve terminals, of 3-month-old DJ-1 KO rats. In total, 371 mitochondrial proteins were quantified, and of these 76 were differentially expressed in DJ-1 KO rats. Proteins perturbed by the loss of DJ-1 were involved in several mitochondrial functional pathways, including the tricarboxylic acid cycle and electron transport chain. Thus, synaptic mitochondrial respiration was measured and showed a significant change due to DJ-1 deficiency. The dataset generated here highlights the role of synaptic mitochondria in PD associated with DJ-1. This study improves our understanding of DJ-1 effects in a complex tissue environment and the synaptic mitochondrial changes that accompany its loss.
Highlights
DJ-1 is a multifunctional protein affecting different biological and cellular processes
Related alterations in the nigrostrial pathway involve the loss of dopaminergic neuronal cell bodies in the substantia nigra pars compacta (SNpc) and their associated nerve terminals in the striatum, we hypothesized that striatal synaptic mitochondria may be affected early in the disease process
We first examined the protein composition of these mitochondria, quantifying the striatal synaptic mitochondrial proteome in male wild-type (WT) and DJ-1 KO rats at 3 months, an age prior to reported motor deficits that start at 4 months, and significant neuronal loss observed at 8 months[15]
Summary
DJ-1 is a multifunctional protein affecting different biological and cellular processes. DJ-1 is expressed in an almost all cells and tissues, including the brain[4], and at the subcellular level is found in the cytoplasm, as well as the mitochondrial intermembrane space and m atrix[3] Bonifati and his colleagues in 2003 discovered that mutations in the gene Park[7], which encodes the protein DJ-1, are linked with an early onset form of recessive P D5. DJ-1 KO rats display significant motor impairments starting at 4 months[15] In both familial and sporadic PD, defects in mitochondria have been well-documented, and mitochondrial alterations have been reported in animal models of P D16–18. We studied the proteomic and bioenergetic properties of striatal synaptic mitochondria from young adult rats, before the onset of neuronal loss due to deficiency in DJ-1
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