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.

Main achievements

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). We identified an interaction between the levels of C9orf72 and the AD-associated amyloid precursor protein (APP) and β-amyloid (Aβ) in cells and human brain, which suggests that altered C9orf72 levels may lead to cell-type specific alterations in APP processing and Aβ generation. 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. 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.

We have also identified several new genes that modulate or associate with the risk of AD in humans and characterized their molecular mechanisms in neurodegeneration and how they influence the already known molecular players in AD pathogenesis, such as APP, Aβ, tau, β-secretase (BACE1), or presenilin-1 (PS1), a key component of the γ-secretase complex, 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. These examinations have allowed us to identify specific genes, e.g. SEPT8, or gene sets, whose expression is altered early during the AD pathogenesis, and helped to predict a time line 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.

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.

Methods

  • 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

Current projects

  • 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

Selected publications

  • Molecular Mechanisms of Synaptotoxicity and Neuroinflammation in Alzheimer's Disease. Marttinen M, Takalo M, Natunen T, Wittrahm R, Gabbouj S, Kemppainen S, Leinonen V, Tanila H, Haapasalo A, Hiltunen M. Front Neurosci. 2018 Dec 14;12:963. doi: 10.3389/fnins.2018.00963. eCollection 2018. Review.
  • A multiomic approach to characterize the temporal sequence in Alzheimer's disease-related pathology. Marttinen M, Paananen J, Neme A, Mitra V, Takalo M, Natunen T, Paldanius KMA, Mäkinen P, Bremang M, Kurki MI, Rauramaa T, Leinonen V, Soininen H, Haapasalo A, Pike I, Hiltunen M. Neurobiol Dis. 2018 Dec 15;124:454-468. doi: 10.1016/j.nbd.2018.12.009.
  • The Association Between Frontotemporal Lobar Degeneration and Bullous Pemphigoid. Katisko K, Kokkonen N, Krüger J, Hartikainen P, Koivisto AM, Helisalmi S, Korhonen VE, Kokki M, Tuusa J, Herukka SK, Solje E, Haapasalo A, Tasanen K, Remes AM. J Alzheimers Dis. 2018;66(2):743-750. doi: 10.3233/JAD-180624.
  • 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.
  • Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. Katisko K, Haapasalo A, Koivisto A, Krüger J, Hartikainen P, Korhonen V, Helisalmi S, Herukka SK, Remes AM, Solje E. J Alzheimers Dis. 2018;62(2):789-794. doi: 10.3233/JAD-170854
  • 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.
  • PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Gubert Olivé M, Shakirzyanova A, Leskelä S, Sarajärvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang SC, Kanninen KM, Hämäläinen RH, Koistinaho J. Stem Cell Reports. 2017 Dec 12;9(6):1885-1897. doi: 10.1016/j.stemcr.2017.10.016.
  • DHCR24 exerts neuroprotection upon inflammation-induced neuronal death. Martiskainen H*, Paldanius KMA*, Natunen T, Takalo M, Marttinen M, Leskelä S, Huber N, Mäkinen P, Bertling E, Dhungana H, Huuskonen M, Honkakoski P, Hotulainen P, Rilla K, Koistinaho J, Soininen H, Malm T, Haapasalo A*, Hiltunen M*. J Neuroinflammation. 2017 Nov 7;14(1):215. doi: 10.1186/s12974-017-0991-6.*Equal contribution.
  • SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1. Kurkinen KM*, Marttinen M*, Turner L, Natunen T, Mäkinen P, Haapalinna F, Sarajärvi T, Gabbouj S, Kurki M, Paananen J, Koivisto AM, Rauramaa T, Leinonen V, Tanila H, Soininen H, Lucas FR, Haapasalo A*, Hiltunen M*. J Cell Sci. 2016 Jun 1;129(11):2224-38. doi: 10.1242/jcs.185215. *Equal contribution.
  • Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models. Natunen T*, Takalo M*, Kemppainen S, Leskelä S, Marttinen M, Kurkinen KMA, Pursiheimo JP, Sarajärvi T, Viswanathan J, Gabbouj S, Solje E, Tahvanainen E, Pirttimäki T, Kurki M, Paananen J, Rauramaa T, Miettinen P, Mäkinen P, Leinonen V, Soininen H, Airenne K, Tanzi RE, Tanila H, Haapasalo A*, Hiltunen M*. Neurobiol Dis. 2016 Jan;85:187-205. doi: 10.1016/j.nbd.2015.11.005. *Equal contribution.
  • Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models. Martiskainen H, Viswanathan J, Nykänen NP, Kurki M, Helisalmi S, Natunen T, Sarajärvi T, Kurkinen KM, Pursiheimo JP, Rauramaa T, Alafuzoff I, Jääskeläinen JE, Leinonen V, Soininen H, Haapasalo A, Huttunen HJ, Hiltunen M. Neurobiol Aging. 2015 Feb;36(2):1221.e15-28. doi: 10.1016/j.neurobiolaging.2014.09.003.
  • Genetic and molecular aspects of frontotemporal lobar degeneration. Review. Haapasalo A, Remes AM.  Current Genetic Medical Reports. 2015. 3:8–182014. doi: 10.1007/s40142-014-0063-5.