Proteomic analysis of <i>parkin</i> knockout mice: alterations in energy metabolism, protein handling and synaptic function

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<jats:title>Abstract</jats:title><jats:p> <jats:italic>Parkin</jats:italic> knockout (KO) mice show behavioural and biochemical changes that reproduce some of the presymptomatic aspects of Parkinson's disease, in the absence of neuronal degeneration. To provide insight into the pathogenic mechanisms underlying the preclinical stages of <jats:italic>parkin</jats:italic>‐related parkinsonism, we searched for possible changes in the brain proteome of <jats:italic>parkin</jats:italic> KO mice by means of fluorescence two‐dimensional difference gel electrophoresis and mass spectrometry. We identified 87 proteins that differed in abundance between wild‐type and <jats:italic>parkin</jats:italic> KO mice by at least 45%. A high proportion of these proteins were related to energy metabolism. The levels of several proteins involved in detoxification, stress‐related chaperones and components of the ubiquitin–proteasome pathway were also altered. These differences might reflect adaptive mechanisms aimed at compensating for the presence of reactive oxygen species and the accumulation of damaged proteins in <jats:italic>parkin</jats:italic> KO mice. Furthermore, the up‐regulation of several members of the membrane‐associated guanylate kinase family of synaptic scaffold proteins and several septins, including the Parkin substrate cell division control related protein 1 (CDCRel‐1), may contribute to the abnormalities in neurotransmitter release previously observed in <jats:italic>parkin</jats:italic> KO mice. This study provides clues into possible compensatory mechanisms that protect dopaminergic neurones from death in <jats:italic>parkin</jats:italic> KO mice and may help us understand the preclinical deficits observed in <jats:italic>parkin</jats:italic>‐related parkinsonism.</jats:p>

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