Protein and MRI profiling of genetic frontotemporal dementia

Frontotemporal dementia (FTD) is a group of neurodegenerative diseases with a wide range of symptoms such as loss of inhibition and social cognition, language impairment and motor dysfunction. Genetic FTD, characterized by mutations in one of several disease-causing genes, accounts for 10 - 30% of all cases of FTD. The most common causes for genetic FTD are repeat expansions in C9orf72 and mutations in GRN or MAPT, but there are also many other, rarer causes. Each mutation gives rise to a specific subtype of genetic FTD. These subtypes differ not only in clinical presentation, but also in the underlying pathophysiology. To be able to study, and eventually treat, genetic FTD a thorough understanding of the genetic subtypes is crucial.

In this thesis we characterized the effects of a p.Ala417* mutation in TBK1, showing that it causes haploinsufficiency as well as demonstrating systemic effects on the K63 ubiquitination system. We also analyzed blood and cerebrospinal fluid samples from carriers of pathogenic mutations associated with genetic FTD to find biomarkers that can distinguish symptomatic mutation carriers from healthy controls or distinguish between the different genetic subtypes. We also studied how these biomarker candidates correlate with cortical and subcortical atrophy in genetic FTD. The results of these studies have provided a further understanding of genetic FTD as well as new biomarker candidates for several pathological processes.

List of scientific papers

I. Khoshnood B, Ullgren A, Laffita-Mesa J, Öijerstedt L, Patra K, Nennesmo I, Graff C. TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers. J Neurol. 2022 Jun;269(6):3037-3049.
https://doi.org/10.1007/s00415-021-10887-x

II. Remnestål J*, Öijerstedt L*, Ullgren A, Olofsson J, Bergström S, Kultima K, Ingelsson M, Kilander L, Uhlén M, Månberg A, Graff C#, Nilsson P#. Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers. Transl Neurodegener. 2020 Jun 23;9(1):27. *Shared first author, #Shared last author.
https://doi.org/10.1186/s40035-020-00198-y

III. Ullgren A*, Öijerstedt L*, Olofsson J, Bergström S, Remnestål J, van Swieten JC, Jiskoot LC, Seelaar H, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Synofzik M, Galimberti D, Rowe JB, Masellis M, Tartaglia MC, Finger E, Vandenberghe R, de Mendonça A, Tirabosch P, Santana I, Ducharme S, Butler CR, Gerhard A, Otto M, Bouzigues A, Russell L, Swift IJ, Sogorb-Esteve A, Heller C, Rohrer JD, Månberg A, Nilsson P, Graff C. Altered plasma protein profiles in genetic FTD – a GENFI study. Mol Neurodegener. 2023 Nov 15;18(1):85. *Shared first author.
https://doi.org/10.1186/s13024-023-00677-6

IV. Ullgren A, Rydell MT, Bergström S, Öijerstedt L, Olofsson J, Bouzigues A, Russell L, Foster P, Ferry-Bolder E, van Swieten J, Jiskoot L, Seelaar H, Sanchez-Valle R, Laforce R, Galimberti D, Vandenberghe R, Gerhard A, Ducharme S, Butler C, Finger E, Tartaglia MC, Masellis M, Rowe J, Synofzik M, Moreno F, Borroni B, Rohrer J, Månberg A, Rodriguez-Vieitez E, Nilsson P, Westman E, Graff C. CSF protein biomarkers associate with cortical and subcortical atrophy: a GENFI study. [Manuscript]