Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death

Syndromes parkinsoniens atypiques en Guadeloupe

[Résumé en français]258 patients ont été suivis dans le service de neurologie du CHU de Pointe à Pitre de 1996 à 2002 parce qu'ils étaient porteurs d'un syndrome parkinsonien. Cette étude a révélé que contrairement à l'Europe et aux États-Unis, la MPI ne constitue pas la principale forme de syndrome parkinsonien. En effet, ce sont les syndromes parkinsoniens atypiques qui sont le plus souvent retrouvé chez les patients guadeloupéens (77,14% des cas). Le syndrome parkinsonien le plus représenté en Guadeloupe (39,15%) ne répond à aucune classification de syndromes parkinsoniens définis jusqu'ici, il est dit " inclassable ". Le deuxième sous-groupe le plus rencontré est la PSP (22,09%). Les formes atypiques de syndrome parkinsonien se distinguent de la MPI selon trois principaux critères : l'asymétrie de la triade parkinsonienne ; la précocité et la sévérité des troubles cognitifs (troubles mnésiques, praxiques, mais surtout un syndrome dysexécutif d'origine frontale) ; la mauvaise réponse à la dopathérapie. Sur l'île de Guam, dans l'océan Pacifique, on isole également un foyer de syndrome parkinsonien atypique, le complexe parkinson-démence, qui se rapproche du syndrome parkinsonien guadeloupéen. Dans ces deux foyers géographiques, la responsabilité d'une toxicité environnementale a été évoquée, mais l'origine multifactorielle des syndromes parkinsoniens, typiques ou non, tend à se confirmer. Il serait intéressant de poursuivre des recherches sur le syndrome parkinsonien guadeloupéen afin d'en améliorer la connaissance et donc la prise en chargePARIS13-BU Serge Lebovici (930082101) / SudocABYMES-CHRUPPA-BU (971202102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Prévalence de la paralysie supranucléaire progressive dans la commune de Wattrelos et sa périphérie et étude clinique auprès des patients

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Un cluster géographique de paralysie supranucléaire progressive dans le nord de la France

International audienceObjective: To describe a cluster of progressive supranuclear palsy (PSP) in northern France. PSP has not been reported in geographical, temporal, or occupational clusters. A unit of Neurology and Neurogeriatrics opened in 2005 at the Centre Hospitalier de Wattrelos, serving the population of Wattrelos and Leers (combined population 51,551) and parts of neighboring towns. For most of the 20th century, this area was a center for chromate and phosphate ore processing, textile dyeing, and tanning. Significant industrial waste persists close to residential areas. Methods: From 2005 to 2014, 92 patients with PSP at Centre Hospitalier de Wattrelos were identified and studied. Detailed residential data were available in the medical records. Eighty cases have had magnetic resonance head scanning and 60 have died, of whom 13 have been examined neuropathologically. Results: The ratio of observed to expected PSP incidence over the period 2005 to 2012 was 12.3 (95% confidence interval: 7.4–35.9). Mean onset age was 74.3 years. The Richardson syndrome/PSP-parkinsonism ratio was 43%/42%. Four other phenotypes each occurred in 2% to 5%. Onset was gait/balance difficulty in 52%. None of the 92 affected patients were relatives and 7 were of North African ancestry. MRI was compatible with a clinical diagnostic of PSP in all cases. Histopathologic examination confirmed neurofibrillary degeneration and tufted astrocytes in all autopsied cases. Western blots revealed a typical tau 4R doublet. The tau H1 haplotype occurred in 95.8% of cases' chromosomes. Conclusions: We have identified a cluster of PSP in a geographical area with severe environmental contamination by industrial metals

L'utilisation d'un promoteur alternatif de MAPT génère de nouveaux transcrits ARNm plus courts dans le cerveau des malades d'Alzheimer et de paralysie supranucléaire progressive

International audienceAlternative promoter usage is an important mechanism for transcriptome diversity and the regulation of gene expression. Indeed, this alternative usage may influence tissue/subcellular specificity, protein translation and function of the proteins. The existence of an alternative promoter for MAPT gene was considered for a long time to explain differential tissue specificity and differential response to transcription and growth factors between mRNA transcripts. The alternative promoter usage could explain partly the different tau proteins expression patterns observed in tauopathies. Here, we report on our discovery of a functional alternative promoter for MAPT, located upstream of the gene's second exon (exon 1). By analyzing genome databases and brain tissue from control individuals and patients with Alzheimer's disease or progressive supranuclear palsy, we identified novel shorter transcripts derived from this alternative promoter. These transcripts are increased in patients' brain tissue as assessed by 5'RACE-PCR and qPCR. We suggest that these new MAPT isoforms can be translated into normal or amino-terminal-truncated tau proteins. We further suggest that activation of MAPT's alternative promoter under pathological conditions leads to the production of truncated proteins, changes in protein localization and function, and thus neurodegeneration

The MAPT gene is differentially methylated in the progressive supranuclear palsy brain

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease causing parkinsonian symptoms. Altered DNA methylation of the microtubule-associated protein tau gene correlates with the expression changes in Alzheimer's disease and Parkinson's disease brains. However, few studies examine the sequences beyond the constitutive promoter