Helena Karlström Group

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 role 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, vaccine development and drug discovery competence.  

Group members

Name Position
Helena Karlström Assoc. Prof. Groupleader
Kirsten Coupland PhD, Postdoc
Daniel Oliveira MSc, PhD student

Dissertations

Helena Karlström, Sep 20, 2002 

Tobias Weber,Sep 25, 2009

Johanna Wanngren, Oct 5, 2012

Annelie Pamrén, Dec 7, 2012

Publications

A sensitive and quantitative assay for measuring cleavage of presenilin substrates.
Karlström H, Bergman A, Lendahl U, Näslund J, Lundkvist J
J. Biol. Chem. 2002 Mar;277(9):6763-6

A sensitive and quantitative assay for measuring cleavage of presenilin substrates.
Karlström H, Bergman A, Lendahl U, Näslund J, Lundkvist J
J. Biol. Chem. 2002 Mar;277(9):6763-6

Functional domains in presenilin 1: the Tyr-288 residue controls gamma-secretase activity and endoproteolysis.
Laudon H, Karlström H, Mathews P, Farmery M, Gandy S, Lundkvist J, et al
J. Biol. Chem. 2004 Jun;279(23):23925-32

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 A, Laudon H, Olsson F, Winblad B, et al
J. Biol. Chem. 2010 Mar;285(12):8527-36

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

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

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

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

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 A, et al
J. Neurosci. 2012 Nov;32(48):17297-305