Brain Advance Access originally published online on May 15, 2006
Brain 2006 129(7):1720-1731; doi:10.1093/brain/awl114
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PINK1 protein in normal human brain and Parkinson's disease
1 Department of Molecular Neuroscience, Institute of Neurology University College London 2 Medical Molecular Biology Unit, Institute of Child Health University College London 3 Queen Square Brain Bank, Institute of Neurology University College London 4 Reta Lila Weston Institute of Neurological Studies University College London 5 Birkbeck College University of London, London, UK
Correspondence to: Professor N Wood, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG E-mail: n.wood{at}ion.ucl.ac.uk
Parkinson's disease is a common incurable neurodegenerative disease whose molecular aetiology remains unclear. The identification of Mendelian genes causing rare familial forms of Parkinson's disease has revealed novel proteins and pathways that are likely to be relevant in the pathogenesis of sporadic Parkinson's disease. Recently, mutations in a novel gene, PINK1, encoding a 581 amino acid protein with both mitochondrial targeting and serine/threonine kinase domains, were identified as a cause of autosomal recessive parkinsonism. This provided important evidence for the role of the mitochondrial dysfunction and kinase pathways in neurodegeneration. In this study, we report the first characterization of the PINK1 protein in normal human and sporadic Parkinson's brains, in addition to Parkinson's cases with heterozygous PINK1 mutations. The possible role of the PINK1 protein was also assessed in a number of neurodegenerative diseases characterized by proteinaceous inclusions. For these studies, rabbit polyclonal antibodies were raised against two peptide sequences within the N-terminal hydrophilic loops of PINK1 protein. Using immunohistochemistry and western blotting we were able to demonstrate that PINK1 is a ubiquitous protein expressed throughout the human brain and it is found in all cell types showing a punctate cytoplasmic staining pattern consistent with mitochondrial localization. Fractionation studies of human and rat brain confirm that PINK1 is localized to the mitochondrial membranes. In addition, we show that PINK1 is detected in a proportion of Lewy bodies in cases of sporadic Parkinson's disease and Parkinson's disease associated with heterozygous mutations in the PINK1 gene, which are clinically and pathologically indistinguishable from the sporadic cases. PINK1 was absent in cortical Lewy bodies, in neurofibrillary tangles in Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, and in the glial and neuronal 
-synuclein positive inclusions in multiple system atrophy. These studies provide for the first time in vivo morphological and biochemical evidence to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.
Key Words: Parkinson's disease; PINK1; immunohistochemistry; genetics; brain
Abbreviations: CBD, corticobasal degeneration; IM, inner mitochondrial membrane; LB, Lewy body; MSA, multiple system atrophy; OM, outer mitochondrial membrane; PINK1-IR, PINK1 immunoreactivity; PSP, progressive supranuclear palsy
Received October 25, 2005. Revised January 29, 2006. Accepted April 4, 2006.
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