Molecular networks and gene identification studies in frontotemporal dementia

Neurodegenerative dementias are a group of disorders that impact people’s daily life by impairing memory, behavior, speech, and ability to perform daily tasks. Although known as the disease of the elderly, early-onset forms affecting the socioeconomically active population aged under 65 years, are increasingly being recognized. In this group, frontotemporal dementia (FTD) is the second most common cause after early-onset Alzheimer’s disease (AD) and is distinguished by development of abnormal behavior and personality, as well as different language impairments and is frequently accompanied by other conditions such as motor neuron disease and parkinsonism, posing a challenge for accurate diagnosis. Up to 40% of FTD patients report at least one first- or second-degree affected relative and autosomal dominant inheritance is more common compared to AD. This strong genetic component has enabled the discovery of mutations in a handful of Mendelian genes. At the same time, the underlying genetic etiology remains elusive in more than half of FTD patients. This missing heritability creates a burden for the patients and caregivers. Efforts to elucidate the missing heritability of FTD gave rise to large-scale genotyping and sequencing projects producing a wealth of data. At this stage, the problem lies in the interpretation of these extensive data sets in relevance to FTD disease biology. Previous research on known disease genes has demonstrated that genes associated with the same disease interact more frequently with each other in converging cellular processes. This has led to the growing field of ‘network medicine’ with various applications from candidate disease gene prioritization to identification of disease-causing mechanisms and development of therapeutic targets. Led by the ‘guilty-by-association’ principle, the assumption that undiscovered disease genes reside in the neighborhood of known disease genes, several new pipelines have been developed to construct disease networks and identify candidate genes for complex diseases. In this PhD project, I aimed to further elucidate the missing heritability of FTD by zooming into molecular disease networks in combination with cohort-based gene identification strategies. I hypothesized that interactors of established FTD proteins are strong candidates to play a role in disease development. To this end, I worked on developing an automated pipeline for protein interaction network analysis and gene prioritization for downstream rare-variant burden analysis on exome data in collaboration with Dr. Claudia Manzoni from the School of Pharmacy, University College London. We created an FTD protein interaction network (FTD-PIN) around previously established FTD genes. Using these genes as seeds, I downloaded experimentally validated direct physical interactors of i) the seeds (1st layer), and ii) their interactors’ (2nd layer). To ensure the reliability and specificity, I submitted this network to several quality steps and retained the interactors common to multiple FTD seeds that are expressed in the brain regions affected in FTD (frontal and temporal lobe). This FTD-PIN served as the basis for identifying biological processes that are implicated in FTD. This pointed to cellular waste disposal, immune system signaling in response to stimulus, and cell death as biological disease processes of interest. By analyzing the rare coding variation in the genes contributing to these prioritized biological processes in a whole exome sequencing dataset of FTD patients and controls, I found evidence for enrichment of rare variants in the TNFAIP3 gene in FTD patients. Interestingly, the TNFAIP3 protein plays an important role in neuroinflammation and variants in this gene were previously associated with an autoimmune disease. This finding is in line with other studies supporting a central role for the immune system and neuroinflammation in FTD pathogenesis. Based on this, we propose TNFAIP3 as an interesting candidate for FTD, meriting further investigation in larger datasets. Alterations in the immune system has been one of the emerging themes in FTD and dementia research. In this context, I performed a follow-up analysis on a recently suggested age at onset modifier locus in patients with a C9orf72 repeat expansion, the leading genetic cause in FTD and amyotrophic lateral sclerosis (ALS). Genetic variants in this modifier locus were proposed to alter disease onset by influencing the expression of a human leukocyte antigen (HLA) gene, an important regulator of the immune system. Even though we tested an extended Belgian C9orf72 mutation carrier cohort, we could not replicate this association in our study (Koçoğlu et al., Neurobiology of Aging 2021), indicating that this locus alone is probably not sufficient to predict the highly variable onset ages observed in C9orf72-related FTD and ALS and underscoring the complexity of such genotype-phenotype correlations. Another pathway of interest in neurodegenerative dementia is that of the endo-lysosomal system. In the context of a JPND (EU Joint Programme–Neurodegenerative Disease Research) funded program, we collaborated with the team of Dr. Roberta Ghidoni and Dr. Luisa Benussi from IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, to investigate the shared genetic variation within endo-lysosomal pathway genes across neurodegenerative dementias. In this ongoing research, we found evidence for enrichment of missense variants in the AP2A2 gene in multiple cohorts of dementia patients (AD, FTD and dementia with Lewy bodies). The AP2A2 protein is part of a crucial protein complex in the endocytosis machinery responsible for the internalization of proteins implicated in AD pathology, making it a strong functional candidate gene for dementia and neurodegeneration. Over the different research lines, our findings have demonstrated that zooming into molecular interaction networks and disease pathways is a powerful approach to identify disease-relevant genetic variations to unravel the missing heritability of complex genetic diseases, such as FTD. This is particularly important to better understand the role of low-effect size variants in disease development, which can open avenues for targeted therapy development.

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open