Molecular Neurodegeneration // Science
Scope of the research
Our research interests lie in the molecular mechanisms underlying the pathogenesis of neurodegenerative disorders, especially frontotemporal dementia (FTD) and Alzheimer's disease (AD). We are also interested in common mechanisms and comorbid features between different neurodegenerative diseases.
Neurodegenerative disorders are common in the aging population. However, especially FTD often has an early onset before the age of 65 years and therefore it may afflict people who are still active in the working life. Currently, there are no available disease-modifying therapies to slow down or stop the disease pathogenesis and there is a great need for specific predictive and/or diagnostic biomarkers for FTD and AD.
We aim at identifying new molecular targets and pathways, which partake in neurodegeneration and underlie the clinical manifestations of FTD or AD. Our goal is to decipher the specific mechanisms how and why these targets affect the pathogenic events taking place in FTD or AD at the molecular level in different types of brain cells. This knowledge is expected to aid in the future development of new biomarkers or therapeutic strategies for FTD and AD.
The most common cause underlying FTD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in the C9orf72 gene. Whereas the other known FTD mutations are extremely rare in Finland, approximately 50% of Finnish FTD patients who show familial inheritance and over 20% of sporadic FTD patients without an apparent family history of neurodegenerative disease are carriers of the C9orf72 repeat expansion. Previous studies at UEF have shown that approximately 25% of Finnish FTD patients with the C9orf72 expansion show decreased CSF Aβ42 levels similarly to patients with Alzheimer’s disease (AD). Our studies in cells and human brain have suggested that altered C9orf72 levels may lead to alterations in the AD-associated amyloid precursor protein (APP) processing and β-amyloid (Aβ) generation in different cells (Leskelä et al., J Alzheimers Dis, 2018). We have recently showed that C9orf72 proteins regulate autophagy and undergo autophagosomal or proteasomal degradation in a cell type-dependent manner (Leskelä et al., Cells, 2019). In addition, our studies in a Finnish FTD patient cohort containing C9orf72 repeat expansion carriers and non-carriers have indicated potentially altered immune system function or responses and association to autoimmune diseases, suggesting involvement of immune system dysfunction and neuroinflammation in FTD pathogenesis (e.g., Katisko et al., J Neurol, 2019; Katisko et al., J Neuroimmunol, 2018). Our current studies focus on understanding the effects of the C9orf72 repeat expansion in different cell types using a variety of mouse and human-based model systems.
In collaborative projects, we have characterized molecular mechanisms and effects of several new genes that modulate or associate with the risk of AD in humans on AD molecular pathogenesis by utilizing different cell-based and animal models and in human brain and cerebrospinal fluid (CSF) samples. Examples of these genes include seladin-1/DHCR24 and UBQLN1 (ubiquilin-1). We also have participated in global transcriptomic, proteomic and phosphoproteomic analyses in human brain to characterize expressional changes at different severity phases of the disease (e.g., Marttinen et al., Neurobiol Dis, 2019). These examinations have allowed us to identify specific genes, e.g. SEPT8 (Kurkinen et al., J Cell Sci, 2016), or gene sets, whose expression is altered early during the AD pathogenesis, and helped to predict a timeline for pathogenic events that define different phases of AD progression. These studies have generated novel information on the molecular pathogenic events taking place at different phases during AD pathogenesis and provide new candidates for biomarker and therapy development. We have also collaborated in human induced pluripotent stem cell (iPSC)-related projects on the generation of iPSC-derived astrocytes (Oksanen et al., Stem Cell Rep, 2017) and microglia (Konttinen et al., Stem Cell Rep, 2019).
Research strategy and methods
We use a highly translational approach in our research, proceeding from different cell or tissue culture models to animal models and to patient-derived cells, brain, blood and cerebrospinal fluid (CSF) samples, and clinical data of FTD or AD patients and back (see graph below). We also simulate the prevailing pathological conditions in the brains of patients with FTD or AD in our model systems.
- Overexpression or downregulation (RNAi) of targets of interest (transfection or virus vector-mediated transduction)
- Modeling neurodegenerative-disease associated stress conditions (e.g. neuroinflammation, excitotoxicity, ER stress, proteostatic stress, modulation of autophagy)
- Analyses of mRNA and protein expression, half-life, activity, and protein-protein interactions (Quantitative PCR, Western blotting, cycloheximide time course, co-immunoprecipitation, cell surface biotinylation, ELISA, enzyme activity assays)
- Subcellular and synaptosomal fractionation
- Cell viability and function assays (e.g. survival, phagocytosis, migration)
- Dendritic spine analysis in neurons
- Immunofluorescence and immunohistochemical staining of cells and tissue samples
- Fluorescence and confocal microscopical analyses of cell morphology and subcellular localization of proteins
- Physiological function and regulation of C9orf72
- Molecular mechanisms of C9orf72 repeat expansion in FTD
- Effects of C9orf72 repeat expansion on neurons
- Effects of C9orf72 repeat expansion on glial cells
- Genes and factors involved in neurodegeneration in AD
- C9orf72 Proteins Regulate Autophagy and Undergo Autophagosomal or Proteasomal Degradation in a Cell Type-Dependent Manner. Leskelä S, Huber N, Rostalski H, Natunen T, Remes AM, Takalo M, Hiltunen M, Haapasalo A. Cells. 2019 Oct 10;8(10). pii: E1233. doi: 10.3390/cells8101233.
- Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders. Katisko K, Cajanus A, Jääskeläinen O, Kontkanen A, Hartikainen P, Korhonen VE, Helisalmi S, Haapasalo A, Koivumaa-Honkanen H, Herukka SK, Remes AM, Solje E. J Neurol. 2019 Oct 8. doi: 10.1007/s00415-019-09567-8.
- Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients. Jääskeläinen O, Solje E, Hall A, Katisko K, Korhonen V, Tiainen M, Kangas AJ, Helisalmi S, Pikkarainen M, Koivisto A, Hartikainen P, Hiltunen M, Ala-Korpela M, Soininen H, Soininen P, Haapasalo A, Remes AM, Herukka SK. J Alzheimers Dis. 2019 Sep 19. doi: 10.3233/JAD-190132.
- Peripheral inflammatory markers and clinical correlations in patients with frontotemporal lobar degeneration with and without the C9orf72 repeat expansion. Katisko K, Solje E, Korhonen P, Jääskeläinen O, Loppi S, Hartikainen P, Koivisto AM, Kontkanen A, Korhonen VE, Helisalmi S, Malm T, Herukka SK, Remes AM, Haapasalo A.J Neurol. 2019 Sep 26. doi: 10.1007/s00415-019-09552-1.
- PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Konttinen H, Cabral-da-Silva MEC, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, Giugno R, Ishchenko Y, Hernández D, Fazaludeen MF, Eamen S, Budia MG, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, Hewitt AW, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pébay A, Koistinaho J, Ooi L, Malm T. Stem Cell Reports. 2019 Oct 8;13(4):669-683. doi: 10.1016/j.stemcr.2019.08.004. Epub 2019 Sep 12.
- Prodromal and Early bvFTD: Evaluating Clinical Features and Current Biomarkers. Katisko K, Cajanus A, Korhonen T, Remes AM, Haapasalo A, Solje E. Front Neurosci. 2019 Jun 21;13:658. doi: 10.3389/fnins.2019.00658. eCollection 2019. Review.
- Astrocytes and Microglia as Potential Contributors to the Pathogenesis of C9orf72 Repeat Expansion-Associated FTLD and ALS. Rostalski H, Leskelä S, Huber N, Katisko K, Cajanus A, Solje E, Marttinen M, Natunen T, Remes AM, Hiltunen M, Haapasalo A. Front Neurosci. 2019 May 15;13:486. doi: 10.3389/fnins.2019.00486. eCollection 2019. Review.
- Mutation Analysis of the Genes Linked to Early Onset Alzheimer's Disease and Frontotemporal Lobar Degeneration. Luukkainen L, Helisalmi S, Kytövuori L, Ahmasalo R, Solje E, Haapasalo A, Hiltunen M, Remes AM, Krüger J. J Alzheimers Dis. 2019;69(3):775-782. doi: 10.3233/JAD-181256.
- Prevalence of immunological diseases in a Finnish frontotemporal lobar degeneration cohort with the C9orf72 repeat expansion carriers and non-carriers. Katisko K, Solje E, Koivisto AM, Krüger J, Kinnunen T, Hartikainen P, Helisalmi S, Korhonen V, Herukka SK, Haapasalo A, Remes AM. J Neuroimmunol. 2018 Aug 15;321:29-35. doi: 10.1016/j.jneuroim.2018.05.011.
- Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples. Leskelä S, Takalo M, Marttinen M, Huber N, Paananen J, Mitra V, Rauramaa T, Mäkinen P, Leinonen V, Soininen H, Pike I, Remes AM, Hiltunen M, Haapasalo A. J Alzheimers Dis. 2018;62(1):269-278. doi: 10.3233/JAD-170362.