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Modulation of endoplasmic reticulum-mitochondria interactions by tauopathy-associated mutations

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  1. Tez No: 519548
  2. Yazar: SAFİYE SERDENGEÇTİ
  3. Danışmanlar: Dr. DAWN LAU
  4. Tez Türü: Yüksek Lisans
  5. Konular: Nöroloji, Neurology
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2016
  8. Dil: İngilizce
  9. Üniversite: King's College London
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 46

Özet

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Özet (Çeviri)

Neurodegenerative diseases are a major cause of disability in aging population worldwide with a wide spectrum of disorders afflicting not only people's physical and mental health but also having a high cost for economy globally. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis in association with frontotemporal dementia (ALS/FTD) are the most common forms of neurodegeneration. All of these diseases are characterised by disruptions of many cellular processes and functions in different forms throughout the brain. Even though these diseases have clinically distinct progressive degeneration and impact different regions of the brain, several studies demonstrated that many of the functions perturbed in these neurodegenerative diseases seem to be regulated by interactions of mitochondria with specific regions of the endoplasmic reticulum. This interaction site has been titled mitochondria-associated ER membranes (MAM), and several studies have also shown that many cellular dysfunctions take place when ER-mitochondria contacts are perturbed in neurodegenerative diseases. These findings suggest a common mechanism that should be investigated to understand the progression of neurodegeneration and find new targets to develop better treatments. In this project, we have investigated whether pathogenic tau has an impact on ER-mitochondria interactions, focusing on tethering proteins in MAM site vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51). Different methods were used to look into VAPB-PTPIP51 binding with luciferase assay on HEK293 cells, colocalisation of VAPBPTPIP51 with immunocytochemistry analysis and Immunofluorescent microscopy imaging on SH-SY5Y cells, and VAPB-PTPIP51 protein expression with western blotting on HEK293 and SH-SY5Y cells. In all experiments, cells were transfected with empty vector for control, WT tau, P301L tau and R406W tau mutations. Our results showed an increased binding between VAPB-PTPIP51 in mutant cells, especially R406W tau condition. However, no change in colocalisation of VAPB-PTPIP51 has been detected in immunocytochemistry experiment. VAPB and PTPIP51 protein expressions in western blots demonstrated no change in the presence of tau mutations, which were consistent with the findings of previous studies on other disease inducing proteins. Even though these results do not show very solid evidence for tau-induced changes in ER-mitochondria interactions, with modulations in experimental methods, these results can be a step forward in investigating tau-induced changes in a common mechanism that is disrupted in many neurodegenerative diseases. Understanding the function and dysfunction of MAM tethering site might present a highly promising target for developing future therapeutic approaches in the treatment of both tauopathies and other related neurodegenerative diseases.

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