Associated group: Neuronal Signaling
We study basic mechanisms underlying neurodegenerative diseases and nerve cell damage in the brain. We focus on protein ubiquitination and the role of mitochondrial and endoplasmic reticulum (ER) stress pathways as well as autophagy in the pathogenesis and models of brain diseases, and employ various proteomic and gene expression methods, cell culture and animal models of disease and genetically modified mice. Although the majority of the group is housed in the Institute of Biomedicine, Faculty of Medicine, the group is actively engaged in research at Minerva.
USP14 and protein ubiquitination in neurodegenerative disorders
Disturbances in protein homeostasis are associated with diseases such as cancer and neurodegenerative disorders. The deubiquitinating enzyme USP14 is associated with the proteasome and influences proteostasis (Srinivasan et al, 2023). Usp-14 is expressed in brain and we observed that Usp-14 reduces mutant Htt aggregates (Hyrskyluoto et al, 2014). Usp14 can also influence autophagy flux via the autophagy-associated protein LC3B (Srinivasan et al, 2020). Using gene deletion of USP14 we have recently discovered novel functions of USP14 in cell physiology including effects on mitochondria and lysosomes that are currently under investigations.
CNPY2 in neuroprotection and ER stress
Canopy Homolog 2 (CNPY2) is an ER resident protein involved in cell mobility, cancer and lipoprotein metabolism (Do e al,2012). Overexpression of CNPY2 is protective whilst downregulation of is detrimental for neurons and CNPY2 could provide some benefit in disorders characterized by loss of neurons such as Huntington´s disease (HD). We are currently studying the transgenic N171-82Q mouse as a model for HD using different protein and molecular methods and behavioral tests (Stepanova et al, 2023).
LACTB in mitochondrial physiology
LACTB is a mitochondrial intermembrane space protein that can polymerize into membrane-attached helical filaments with a similarity to bacterial penicillin-binding proteins and beta-lactamases. LACTB has been linked to cancer as a tumor suppressor and to lipid metabolism (Cascone et al, 2022), but the precise physiological functions and possible substrates of LACTB), are unknown. Here we will study these issues further including analyses of LACTB knock-out mice.
Selected publications
Cascone, A., Lalowski, M., Lindholm, D., & Eriksson, O. (2022). Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer. Cells, 11 (10), 1703.
Do, H. T., Tselykh, T. V., Mäkelä, J., Ho, T. H., Olkkonen, V. M., Bornhauser, B. C., Korhonen, L., Zelcer, N. & Lindholm, D. (2012) Fibroblast Growth Factor-21 (FGF21) Regulates Low-density Lipoprotein Receptor (LDLR) Levels in Cells via the E3-ubiquitin Ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting Saposin-like Protein (Msap). J Biol Chem. 287, 12602-12611
Hyrskyluoto A, Bruelle C, Lundh SH, Do HT, Kivinen J, Rappou E, Reijonen S, Waltimo T, Petersén Å, Lindholm D, Korhonen L. (2014) Ubiquitin specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1a. Hum Mol Genetics 23, 5928-5939.
Korhonen L, Paul ER, Karin Wåhlén K, Haring L, Vasar E, Vaheri A, Lindholm D. (2023) Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients. Translational Psychiatry, 13(1):326.doi 10.1038/s41398-023-02627-8
Lindholm D, Korhonen L, Eriksson O, and Kõks S (2017) Recent Insights into the Role of Unfolded Protein Response in ER stress in Health and Disease. Frontiers in Cell and Dev. Biol., 5:48.
Pham DD, Bruelle C, Thi Do H, Pajanoja C, Jin C, Srinivasan V, Olkkonen VM, Eriksson O, Jauhiainen M, Lalowski M, Lindholm D. (2019) Caspase-2 and p75 neurotrophin receptor (p75NTR) are involved in the regulation of SREBP and lipid genes in hepatocyte cells. Cell Death Dis. 11;10(7):537.
Srinivasan V, Bruelle C, Scifo E, Pham DD, Soliymani R, Lalowski M, Lindholm D. (2020) Dynamic interaction of USP14 with the chaperone HSC70 mediates crosstalk between the proteasome, ER signaling and autophagy. iScience 23(1):100790.
Srinivasan V, Asghar MY, Zafar S, Törnquist K, Lindholm D. (2023) Proliferation and migration of ML1 follicular thyroid cancer cells are inhibited by IU1 targeting USP14: role of proteasome and autophagy flux. Front Cell Dev Biol. 11: 30 aug2023.
Stepanova P, Kumar D, Cavonius K, Korpikoski J, Sirjala J, Lindholm D, Voutilainen MH (2023) Beneficial behavioral effects of cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease. Scientific Report 13:2953.
External funding
Doctoral Programme in Biomedicine (DPBM)
Finnish Society of Sciences and Letters
Magnus Ehrnrooth Foundation
Medical Society of Finland
Medicinska understödsföreningen Liv och Hälsa r.f.
University of Helsinki