Helena Karlström Group

Notch3 and the cerebral small vessel disease CADASIL – from molecular mechanisms to treatment strategies

Research focus

In the Karlström lab we focus on CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the most common familial form of small vessel disease. The condition leads to a series of increasingly severe strokes and dementia. CADASIL is linked to the Notch3 protein which is an important signaling protein allowing cells to communicate with one another. Mutations in the NOTCH3 gene result in misfolded Notch3 accumulating around small and middle-sized arteries throughout the body. At present how these Notch3 deposits affect the surrounding tissues is unclear. The disease mechanisms may be further complicated due to altered Notch3 signalling. A number of genetic disorders such as familial Alzheimer’s disease are directly linked to protein misfolding, which strongly suggest that abnormal protein accumulation and deposits play a direct cytotoxic rile in the disease. 

We aim to better understand the molecular mechanisms of this condition in order to develop therapeutics to tackle CADASIL. We hypothesise that if we can harness the immune system to clear the Notch3 deposits we can halt or potentially reverse CADASIL progression.

A successful treatment for CADASIL would provide a much-needed cure for many individuals and would pave the way for new small vessel disease therapeutics. Our inter-disciplinary project team has clinical and preclinical expertise in CADASIL, and vaccine development and drug discovery competence. 

Group members

Helena Karlström

Senior lecturer

Shao-Bo Jin

Research specialist

Rhys Fox, MSc student

Selected scientific publications

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression.
Panahi M, Yousefi Mesri N, Samuelsson EB, Coupland KG, Forsell C, Graff C, et al
J Cell Mol Med 2018 06;22(6):3016-3024

Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing.
Stanga S, Vrancx C, Tasiaux B, Marinangeli C, Karlström H, Kienlen-Campard P
J Cell Mol Med 2018 02;22(2):823-833

Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production.
Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlström H, et al
J Cell Mol Med 2016 09;20(9):1686-95

Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations.
Wanngren J, Lara P, Ojemalm K, Maioli S, Moradi N, Chen L, et al
FEBS Open Bio 2014 ;4():393-406

Visualizing active enzyme complexes using a photoreactive inhibitor for proximity ligation--application on γ-secretase.
Schedin-Weiss S, Inoue M, Teranishi Y, Yamamoto NG, Karlström H, Winblad B, et al
PLoS One 2013 ;8(5):e63962

Alzheimer's disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy.
Borgegård T, Gustavsson S, Nilsson C, Parpal S, Klintenberg R, Berg AL, et al
J Neurosci 2012 Nov;32(48):17297-305

Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.
Wanngren J, Ottervald J, Parpal S, Portelius E, Strömberg K, Borgegård T, et al
J Biol Chem 2012 Sep;287(39):32640-50

Biochemical studies of poly-T variants in the Alzheimer's disease associated TOMM40 gene.
Hedskog L, Brohede J, Wiehager B, Pinho CM, Revathikumar P, Lilius L, et al
J Alzheimers Dis 2012 ;31(3):527-36

Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing.
Pamrén A, Wanngren J, Tjernberg LO, Winblad B, Bhat R, Näslund J, et al
J Biol Chem 2011 Sep;286(36):31153-8

Minor contribution of presenilin 2 for γ-secretase activity in mouse embryonic fibroblasts and adult mouse brain.
Frånberg J, Svensson AI, Winblad B, Karlström H, Frykman S
Biochem Biophys Res Commun 2011 Jan;404(1):564-8

γ-Secretase complexes containing caspase-cleaved presenilin-1 increase intracellular Aβ(42) /Aβ(40) ratio.
Hedskog L, Petersen CA, Svensson AI, Welander H, Tjernberg LO, Karlström H, et al
J Cell Mol Med 2011 Oct;15(10):2150-63

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.
Luty AA, Kwok JB, Dobson-Stone C, Loy CT, Coupland KG, Karlström H, et al
Ann Neurol 2010 Nov;68(5):639-49

gamma-Secretase dependent production of intracellular domains is reduced in adult compared to embryonic rat brain membranes.
Frånberg J, Karlström H, Winblad B, Tjernberg LO, Frykman S
PLoS One 2010 Mar;5(3):e9772

The large hydrophilic loop of presenilin 1 is important for regulating gamma-secretase complex assembly and dictating the amyloid beta peptide (Abeta) Profile without affecting Notch processing.
Wanngren J, Frånberg J, Svensson AI, Laudon H, Olsson F, Winblad B, et al
J Biol Chem 2010 Mar;285(12):8527-36

Peer Review Research Review Articles

Manuscript (sumbitted):

Coupland K. G., Lendahl U., Karlström H. "The role of NOTCH3 mutations in the cerebral small vessel disease CADASIL” Invititation by Stroke


Johanna Wanngren, 2012. Molecular studies of the γ-secretase complex: focus on genetic and pharmacological modulation. 

Annelie Pamrén, 2012. Different types of γ-secretes complexes and their effect on substrate processing.

Content reviewer:
Philipp Kreft