The doctoral dissertation in the field of Neuroscience will be examined at the Faculty of Health Sciences at Kuopio campus. The public examination will be streamed online.
What is the topic of your doctoral research? Why is it important to study the topic?
My doctoral dissertation studied the mechanisms of neurodegeneration in frontotemporal dementia (FTD) with a special focus on synaptic dysfunction. FTD is a neurodegenerative disease which is characterized by loss of neurons, disturbed neuronal function, and accumulation of pathological proteins such as TDP-43. Unfortunately, we do not have any disease modifying drugs or therapies available, the only option are symptomatic treatments. FTD is the most common early-onset dementia in the working age population (<65 years) and composes a cluster of different syndromes with several different clinical phenotypes. The most common genetic mutation leading to FTD is a hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE), which is exceptionally common in the Finnish population, making it extremely relevant to study it here in Finland.
FTD patients show alterations in their personality and behaviour, present with impaired language skills and/or movement disabilities. Those symptoms not only affect the patients, but they also severely affect their families and caregivers. Synaptic dysfunction correlates best with the clinical symptoms observed in patients, however, there is still a lack of understanding how synaptic dysfunction contributes to disease pathogenesis and progression. Therefore, my thesis aimed to better understand the underlying molecular mechanisms of synaptic dysfunction and neurodegeneration in FTD. Another aim of the thesis was to correlate the clinical symptoms of FTD patients to cellular and molecular features and we investigated whether a protein measured from patients’ blood could serve as a biomarker to aid in the identification of specific neuropathological subtypes of FTD patients.
What are the key findings or observations of your doctoral research?
The key findings of my thesis are that synaptic dysfunction appears to be a unifying feature of FTD patients regardless of if they carry an underlying genetic mutation (C9-HRE) or not. The results of my studies also suggest that patient-derived induced pluripotent stem cell-based neurons recapitulate key pathological changes taking place in FTD patients’ brains, and therefore represent valuable disease models for research into disease mechanisms and biomarkers. Another major finding is that TDP-43 protein demonstrates to be a useful blood-based biomarker for discriminating between different FTD subtypes and FTD patients from healthy controls.
How can the results of your doctoral research be utilised in practice?
The results from this doctoral thesis can be used as the basis for following studies especially e.g., when developing new biomarkers or novel therapies targeting the synaptic dysfunction. Also, TDP-43 might represent a biomarker, which may help to estimate the underlying neuropathology already during the lifetime of the patients. This would be important for example for disease prediction.
What are the key research methods and materials used in your doctoral research?
To study the effect of the C9-HRE we utilized mouse primary hippocampal neurons overexpressing the pathological repeat expansion as well as induced pluripotent stem cell (iPSCs) derived neurons from Finnish FTD patients harbouring the C9-HRE, from those with sporadic FTD, the cause of which is unknown, and from healthy controls. First, we validated the cell models by studying the typical C9-HRE-associated FTD cellular hallmarks such as RNA foci and DPR proteins, and further investigated neuronal function and synaptic dysfunction. We also performed global RNA sequencing to identify altered gene expression and biological pathways in the different groups. We found altered neuronal function in both neuronal models, including altered synaptic structures and function. Additionally, we detected changes in TDP-43 subcellular localization, suggesting altered RNA processing, as well as increased accumulation of p62, pointing towards disturbed autophagy. RNA sequencing also revealed gene expression changes in pathways related to synaptic function and DNA damage. Interestingly between the neurons from C9-HRE FTD patients and sporadic FTD patients only one gene was differentially expressed, indicating a potentially altered stress response and increased DNA damage.
Furthermore, we found a strong correlation between the molecular and cellular findings related to genetic and clinical features of the patients. FTD patients with predicted TDP-43 brain pathology showed significantly lower serum TDP-43 levels than healthy controls or FTD patients with tau pathology. Interestingly, the lowest levels of total TDP-43 levels were detected in FTD patients carrying the C9-HRE. This leads to the conclusion that blood-based measurement of TDP-43 enables distinguishing the different neuropathological forms of FTD.
The doctoral dissertation of Nadine Huber, MSc, entitled Mechanisms of neurodegeneration in frontotemporal dementia: Focus on synaptic dysfunction will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Kurt De Vos of Sheffield Institute for Translational Neuroscience (SITraN), and the Custos will be Professor Annakaisa Haapasalo of the University of Eastern Finland.
Doctoral dissertation
For further information, please contact:
Nadine Huber, MSc, nadine.huber@uef.fi, https://uefconnect.uef.fi/en/person/nadine.huber/
