Neurodegenerative disorders in most cases are associated with age which means that despite the role of genetic predisposition and of endogenic and exogenic parameters age as such represents the key risk factor. The research approach of the Behl group to shed light on molecular mechanisms underlying neurodegeneration, therefore, starts with the analysis of the molecular differences of young and aged neurons.
Oxidative stress is an imbalance of the generation and removal of mainly reactive oxygen species (ROS) leading to the oxidation of proteins, lipids and nucleic acids, and is a feature of the physiological aging process per se as well as of several age-associated neurodegenerative disorders. Accordingly, the design and application of novel antioxidants in vitro and in vivo is one of the neuroprotective strategies we pursue.
As a number of age-associated, neurodegenerative as well, diseases is hallmarked by intra- or extracellular protein aggregates (Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis) one focus of our research efforts is on protein homeostasis in neurons. For the maintenance of cellular proteostasis specific protein degradation is crucial. It is accomplished either via the ubiquitin proteasome system or the process of autophagy which encompasses the degradation of cytoplasmic macromolecules or organelles by means of the lysosomal system. The fact that autophagy is increased in aged cells we understand as the cells reaction to the proteotoxic environment that comes along with the aging process.
The modulation of protein degradation processes is managed by the reciprocal regulation of the co-chaperone proteins BAG1 and BAG3 and we were able to describe BAG3-mediated selective macroautophagy as a novel degradation pathway decomposing protein aggregates. Currently, we are characterizing how exactly this process is regulated and what the physiological and pathophysiological functions are. As another challenge for cellular homeostasis we are investigating the enduring shortage of neurons in terms of oxygen and nutrition which is common in old age of man. There, we presently focus on the involvement of autophagic processes in dysfunctional neurotransmission.
Novel components determining cellular protein quality control are identified employing specific C.elegans reporter strains and RNAi libraries. Recently, we were able to characterize the RAB3GAP1/ RAB3GAP2 complex as a new factor of macroautophagy.
All together, our research projects focusing on aging, oxidative stress, protein aggregation and autophagy aim to unravel molecular mechanisms underlying neurodegeneration and are closely intertwined.
Feldmann A, Bekbulat F, Huesmann H, Ulbrich S, Tatzelt J, Behl C, Kern A (2017). The RAB GTPase RAB18 modulates macroautophagy and proteostasis.
Biochem Biophys Res Commun. 2017 Mar 22. [Epub ahead of print]
Schönbühler B, Schmitt V, Huesmann H, Kern A, Gamerdinger M, Behl C (2017). BAG2 Interferes with CHIP-Mediated Ubiquitination of HSP72. Int. J. Mol. Sci. 18(1), 69.
Felzen V, Hiebel C, Koziollek-Drechsler I, Reißig S, Wolfrum U, Kögel D, Brandts C, Behl C, Morawe T (2015). Estrogen receptor α regulates non-canonical autophagy that provides stress resistance to neuroblastoma and breast cancer cells and involves BAG3 function. Cell Death Dis. 6:e1812.
Hajieva P, Bayatti N, Granold M, Behl C, Moosmann B (2015) Membrane protein oxidation determines neuronal degeneration. J Neurochem. 133(3):352-67.
Spang N*, Feldmann A*, Huesmann H, Bekbulat F, Schmitt V, Hiebel C, Koziollek-Drechsler I, Clement AM, Moosmann B, Jung J, Behrends C, Dikic I, Kern A, Behl C (2014). RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy. (* equal contribution) Autophagy. 2014 Dec 12 [Epub ahead of print]
Renziehausen J, Hiebel C, Nagel H, Kundu A, Kins S, Kögel D, Behl C, Hajieva P (2015). The Cleavage Product of Amyloid-β Protein Precursor sAβPPα Modulates BAG3-Dependent Aggresome Formation and Enhances Cellular Proteasomal Activity. J Alzheimers Dis. 44(3):879-96.