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 alpha-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.
We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
We describe four cases of a new clinicopathological entity presenting with either a frontotemporal dementia or corticobasal degeneration syndrome with a mean age of onset of 45 years (range 41-50) characterized pathologically by deposition of neurofilament proteins. All four patients had a rapidly progressive course and have become mute and non-ambulatory, and three have died after mean illness duration of only 3 years (range 2 1/2 -4). Both structural (MRI) and functional (PET and SPECT) imaging demonstrated frontal and temporal lobe and basal ganglia involvement. Gross neuropathological examination in the three deceased patients (the fourth patient, still alive, was diagnosed by brain biopsy) revealed changes affecting predominantly the frontal and temporal cortices, basal ganglia and brainstem. There was superficial linear spongiosis affecting the frontal lobes in all three autopsied patients, and severe caudate atrophy was noted in two of them and demonstrated on MRI in the living patient. On routine staining, there were numerous intracytoplasmic inclusions, which ranged from eosinophilic to basophilic. Some had a clearly defined basophilic margin, while others were granular with a hyaline core. With modified Bielschowsky silver technique, a small number of the inclusions were intensely stained. Inclusions were not labelled with other silver stains. Immuno histochemistry revealed that the inclusions were immunoreactive with antibodies to neurofilament heavy and light chain subunits and to ubiquitin, but not with antibodies to tau and alpha-synuclein. These neurofilament- and ubiquitin-positive inclusions were widespread, specific to neurons and occasionally intranuclear. The frequency and distribution of the inclusions and the silver and immunohistochemical profiles in these four cases is novel and has not been described in detail before. We propose the term neurofilament inclusion body disease for this entity.
Targeted and localized mass spectrometry imaging allows faster characterization of cancer compared to conventional methods.
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