Homira Behbahani Group

Picture of Homira BehbahaniThe role of Omi/HtrA2 in Alzheimers disease, Biological studies of CADASIL

Research focus

Project I. The role of Omi/HtrA2 protease activity on mitochondrial motility in Alzheimers disease

Alzheimers disease (AD) is characterized by progressive memory loss and cognitive impairment. Deficits in mitochondrial function in AD suggest that mitochondria might play a major role in the synaptic alteration seen in AD. Mitochondria are important organelles that mediate energy metabolism, cell signalling and homeostasis in eukaryotic cells. Increasing evidences suggest that mitochondria can be localized in different sub-compartments in different cell types, which differ significantly in their function, morphology and other properties. Neurons are distinct from other eukaryotic cells and require highly energy provision. Therefore mitochondrial distribution and localization in synapses are prerequisite of inter-neuronal communication. Recent study demonstrates that synaptic mitochondria have various sizes, different trafficking patterns, function and life span compared to their relatives in neuronal soma. Neuronal mitochondria thus undergo constant fission and fusion in order to maintain a healthy and mobile network to support synaptic maintenance, bioenergetics and mtDNA. Altered redistribution of mitochondria in neurons in AD patients trigger initiation of studies questioning the molecular mechanism involved in mitochondrial motility in AD.

The serine protease Omi/HtrA2 is localized in the endoplasmic reticulum, nucleus and in mitochondria. Lately, Omi/HtrA2 has been implicated in the pathogenesis of several neurodegenerative disorders suggesting that Omi/HtrA2 plays a neuroprotective role in the central nervous system. Recently, we have reported the role of Omi/HtrA2 protease activity and its association with mitochondrial ³-secretase in AD brain and mouse embryonic fibroblasts. For the present project, we hypothesize that Omi/HtrA2 protease activity can jeopardize the degradation of cytoskeletal proteins in neurons which can disrupt mitochondrial axonal transport and motility. In our group we will study if Omi/HtrA2 protease activity affects mitochondrial motility and distribution and how changes of Omi/HtrA2 protease activity might influence synapse formation and degeneration, both in vitro and in vivo. Identification of the key events in the mitochondrial motility and the role of Omi/HtrA2 protease activity might provide new strategy in treatment of AD patients.

Project II. Toxicity of Notch 3 extracellular domain (N3ECD) on cellular function

Mutations in Notch 3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy leading to strokes and dementia. N3ECD is cleaved after several proteolytic processing steps of the Notch 3 receptor and can appear as granular osmophilic material (GOM) which together with degeneration of vascular smooth muscle cells (VSMCs) showing the key features in CADASIL pathogenesis. Recent data suggest that mutated N3ECD aggregates and forms hetero-, homo-dimers and oligomers, which might be toxic and thereby have a role in CADASIL pathogenesis. A key question is: Do aggregation of N3ECD trigger apoptosis?

In this project we are interested in investigating the effect of N3EDC on cell viability and mitochondrial function in VSMCs. Furthermore, we want to study whether N3ECD will be internalized by the cells and degraded.


This project is in collaboration with Professor Matti Viitanen at division of clinical geriatrics and Associate Professor Erik Sundström at the division of neurodegeneration, and is supported with funding for CADASIL project.

Group members



Homira Behbahani PhD, Associate Professor
Matti Vitanen Professor
Mahmod Panahi PhD student
Sareh Rezaeeyan,  Master Student, Stockholm University
Naeimeh Yousefi Mesri Bergen University


Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells.
Lucotte B, Tajhizi M, Alkhatib D, Samuelsson E, Wiehager B, Schedin-Weiss S, et al
Mol. Neurobiol. 2015 Dec;52(3):1077-92

Regulated Extracellular Choline Acetyltransferase Activity- The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway.
Vijayaraghavan S, Karami A, Aeinehband S, Behbahani H, Grandien A, Nilsson B, et al
PLoS ONE 2013 ;8(6):e65936

Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models.
Hedskog L, Pinho C, Filadi R, Rönnbäck A, Hertwig L, Wiehager B, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 May;110(19):7916-21

Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells.
Viitanen M, Sundström E, Baumann M, Poyhonen M, Tikka S, Behbahani H
Exp. Cell Res. 2013 Feb;319(3):134-43

Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor.
Dehvari N, Mahmud T, Persson J, Bengtsson T, Graff C, Winblad B, et al
Neurochem. Int. 2012 Apr;60(5):533-42

Association of Omi/HtrA2 with γ-secretase in mitochondria.
Behbahani H, Pavlov P, Wiehager B, Nishimura T, Winblad B, Ankarcrona M
Neurochem. Int. 2010 Nov;57(6):668-75

Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease.
Westerlund M, Behbahani H, Gellhaar S, Forsell C, Belin A, Anvret A, et al
FASEB J. 2011 Apr;25(4):1345-52

Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein.
Pavlov P, Wiehager B, Sakai J, Frykman S, Behbahani H, Winblad B, et al
FASEB J. 2011 Jan;25(1):78-88

Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1.
Sandebring A, Thomas K, Beilina A, van der Brug M, Cleland M, Ahmad R, et al
PLoS ONE 2009 May;4(5):e5701

CD147, a gamma-secretase associated protein is upregulated in Alzheimer's disease brain and its cellular trafficking is affected by presenilin-2.
Nahalkova J, Volkmann I, Aoki M, Winblad B, Bogdanovic N, Tjernberg L, et al
Neurochem. Int. 2010 Jan;56(1):67-76

Synaptic and endosomal localization of active gamma-secretase in rat brain.
Frykman S, Hur J, Frånberg J, Aoki M, Winblad B, Nahalkova J, et al
PLoS ONE 2010 Jan;5(1):e8948

The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.
Hansson Petersen C, Alikhani N, Behbahani H, Wiehager B, Pavlov P, Alafuzoff I, et al
Proc. Natl. Acad. Sci. U.S.A. 2008 Sep;105(35):13145-50

Differential role of Presenilin-1 and -2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts.
Behbahani H, Shabalina I, Wiehager B, Concha H, Hultenby K, Petrovic N, et al
J. Neurosci. Res. 2006 Sep;84(4):891-902