Temporal-spatial profiling of pedunculopontine galanin-cholinergic neurons in the lactacystin rat model of Parkinson’s disease

Parkinson’s disease (PD) is conventionally seen as resulting from single-system neurodegeneration affecting nigrostriatal dopaminergic neurons. However, accumulating evidence indicates a multi-system degeneration and neurotransmitter deficiencies, including cholinergic neurons which degenerate in a brainstem nucleus, the pedunculopontine nucleus (PPN), resulting in motor- and cognitive impairments. The neuropeptide galanin can inhibit cholinergic transmission, whilst being upregulated in degenerating brain regions associated with cognitive decline. Here we determined the temporal-spatial profile of progressive expression of endogenous galanin within degenerating cholinergic neurons, across the rostro-caudal axis of the PPN, by utilising the lactacystin-induced rat model of PD. First, we show progressive neuronal death affecting nigral dopaminergic and PPN cholinergic neurons, reflecting that seen in PD patients, to facilitate use of this model for assessing the therapeutic potential of bioactive peptides. Next, stereological analyses of the lesioned brain hemisphere found that the number of PPN cholinergic neurons expressing galanin increased by 11%, compared to sham-lesioned controls, increasing by a further 5% as the neurodegenerative process evolved. Galanin upregulation within cholinergic PPN neurons was most prevalent closest to the intra-nigral lesion site, suggesting that galanin upregulation in such neurons adapt intrinsically to neurodegeneration, to possibly neuroprotect. This is the first report on the extent and pattern of galanin expression in cholinergic neurons across distinct PPN subregions in both the intact rat CNS and lactacystin lesioned rats. The findings pave the way for future work to target galanin signaling in the PPN, to determine the extent to which upregulated galanin expression could offer a viable treatment strategy for ameliorating PD symptoms associated with cholinergic degeneration

MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease. We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS

Tuberculous meningitis in Denmark: a review of 50 cases

<p>Abstract</p> <p>Background</p> <p>Tuberculous meningitis is the most severe manifestation of extrapulmonary tuberculosis with a high mortality rate and a high rate of sequelae among survivors. The aim of this study is to assess the current epidemiology, clinical features, diagnostic procedures, treatment and outcome in patients with tuberculous meningitis in Denmark, a country with a low tuberculosis incidence.</p> <p>Methods</p> <p>A nationwide retrospective study was conducted, comprising all patients notified with tuberculous meningitis (TBM) in Denmark from 2000-2008. Medical records were reviewed using a standardised protocol.</p> <p>Results</p> <p>Fifty patients, including 12 paediatric patients, were identified. 78% of the patients were immigrants from countries of high tuberculosis endemicity. 64% of all patients had a pre-existing immunosuppressive condition; 10% were HIV positive, 48% were HIV seronegative and 42% had an unknown HIV status. Median symptom duration before admission was 14 days in the Danish patient population and 20 days in the immigrant group. Biochemical analysis of cerebrospinal fluid (CSF) samples revealed pleocytosis in 90% with lymphocyte predominance in 66%. Protein levels were elevated in 86%. The most common findings on neuro-radiological imaging were basal meningeal enhancement, tuberculomas and hydrocephalus. Lumbar puncture was performed on 42 patients; 31 of these specimens (74%) had a positive CSF culture for mycobacteria and 9.5% were smear positive for acid-fast bacilli. The overall mortality rate was 19% and 48% of the remaining patients had neurological sequelae of varying degree.</p> <p>Conclusion</p> <p>TBM is a rare but severe manifestation of extrapulmonary TB in Denmark. The clinician must be prepared to treat empirically if the suspicion of TBM has arisen to improve treatment outcome.</p

Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer’s disease are not present in diabetic Alzheimer’s disease

Background: Mitochondrial dysfunction is implicated in both diabetes and Alzheimer’s disease (AD), and diabetes also increases the risk of AD, however the combined impact of AD and diabetes on brain mitochondria is unknown. The purpose of this study was to test the hypothesis that the combination of both diabetes and AD exacerbates mitochondrial dysfunction. Methods: Post-mortem human brains (n=74), were used to determine mitochondrial DNA (mtDNA) content of cerebellum, frontal cortex and parietal cortex by quantifying absolute mtDNA copy number/cell using real time qPCR. mtDNA content was compared between diabetic and non-diabetic cases representing non-cognitively impaired controls (NCI), mildly cognitively impaired (MCI) and AD. A subset of parietal cortex samples was used to quantify mRNAs corresponding to cell types and mitochondrial function. Immune-staining of parietal cortex sections followed by semi-automated stereological assessment was performed to assess cell types. Results. Using mtDNA as an indicator of mitochondrial content, we observed significant regional variation, being highest in the parietal cortex, and lowest in the cerebellum. In the absence of diabetes, AD cases had decreased parietal cortex mtDNA, reduced MAP2 (neuronal) mRNA and increased GFAP (astrocyte) mRNA, relative to NCI. However, in the presence of both diabetes and AD, we did not observe these changes in the parietal cortex. Irrespective of cognitive status, all 3 brain regions in diabetic cases had significantly higher mtDNA than the non-diabetic cases. Conclusion. Our data show that the parietal cortex has the highest mitochondrial content but is also the most vulnerable to changes in AD, as shown by reduced mtDNA and neurones in this region. In contrast, when patients have both diabetes and AD, the AD associated parietal cortex changes are no longer seen, suggesting that the pathology observed in diabetic AD may be different to that seen in non-diabetic AD. The lack of clear functional changes in mitochondrial parameters in diabetic AD suggest that there may be different mechanisms contributing to cognitive impairment in diabetes and their impact on the respective disease neuro-pathologies remain to be fully understood

Comparative mitochondrial proteomics: perspective in human diseases

Mitochondria are the most complex and the most important organelles of eukaryotic cells, which are involved in many cellular processes, including energy metabolism, apoptosis, and aging. And mitochondria have been identified as the "hot spot" by researchers for exploring relevant associated dysfunctions in many fields. The emergence of comparative proteomics enables us to have a close look at the mitochondrial proteome in a comprehensive and effective manner under various conditions and cellular circumstances. Two-dimensional electrophoresis combined with mass spectrometry is still the most popular techniques to study comparative mitochondrial proteomics. Furthermore, many new techniques, such as ICAT, MudPIT, and SILAC, equip researchers with more flexibilities inselecting proper methods. This article also reviews the recent development of comparative mitochondrial proteomics on diverse human diseases. And the results of mitochondrial proteomics enhance a better understanding of the pathogenesis associated with mitochondria and provide promising therapeutic targets

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research