Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity
| العنوان: | Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity |
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| المؤلفون: | Idoia Glaria, Adrian M. Isaacs, Annelies Quaegebeur, Tammaryn Lashley |
| المساهمون: | European Research Council, European Commission, Medical Research Council (UK), Motor Neuron Disease Association, Dementia Research Institute (UK), Alzheimer's Research UK |
| المصدر: | Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-13 (2020) Digital.CSIC. Repositorio Institucional del CSIC instname Acta Neuropathologica Communications |
| بيانات النشر: | BMC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Repetitive Sequences, Amino Acid, Polymers, Dipeptide repeat proteins, medicine.disease_cause, Frontotemporal lobar degeneration, lcsh:RC346-429, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, C9orf72, medicine, Humans, Meso Scale Discovery, Amyotrophic lateral sclerosis, Poly-GR, lcsh:Neurology. Diseases of the nervous system, Aged, 030304 developmental biology, C9orf72 mutation, 0303 health sciences, Mutation, DNA Repeat Expansion, Dipeptide, C9orf72 Protein, Research, Brain, Proteins, Dipeptides, Middle Aged, medicine.disease, 3. Good health, chemistry, Biochemistry, Solubility, Toxicity, Female, Neurology (clinical), Trinucleotide repeat expansion, 030217 neurology & neurosurgery, Frontotemporal dementia |
| الوصف: | A C9orf72 repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. One of the suggested pathomechanisms is toxicity from dipeptide repeat proteins (DPRs), which are generated via unconventional translation of sense and antisense repeat transcripts with poly-GA, poly-GP and poly-GR being the most abundant dipeptide proteins. Animal and cellular studies highlight a neurotoxic role of poly-GR and poly-PR and to a lesser degree of poly-GA. Human post-mortem studies in contrast have been much less clear on a potential role of DPR toxicity but have largely focused on immunohistochemical methods to detect aggregated DPR inclusions. This study uses protein fractionation and sensitive immunoassays to quantify not only insoluble but also soluble poly-GA, poly-GP and poly-GR concentrations in brain homogenates of FTD patients with C9orf72 mutation across four brain regions. We show that soluble DPRs are less abundant in clinically affected areas (i.e. frontal and temporal cortices). In contrast, the cerebellum not only shows the largest DPR load but also the highest relative DPR solubility. Finally, poly-GR levels and poly-GP solubility correlate with clinical severity. These findings provide the first cross-comparison of soluble and insoluble forms of all sense DPRs and shed light on the distribution and role of soluble DPRs in the etiopathogenesis of human C9orf72-FTD. AI receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (648716-C9ND), the Motor Neurone Disease Association and the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. TL is supported by an Alzheimer’s Research UK Senior Fellowship and the Leonard Wolfson Centre for Experimental Neurology. The Queen Square Brain Bank for Neurological Disorders is supported by the Reta Lila Weston Institute of Neurological Studies, UCL Queen Square. |
| اللغة: | English |
| تدمد: | 2051-5960 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e772ddfac2b743b64ac1f376ca07202bTest http://link.springer.com/article/10.1186/s40478-020-01036-yTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e772ddfac2b743b64ac1f376ca07202b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20515960 |
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