Karin Hochrainer, Ph.D.
Assistant Professor of Neuroscience
Finbar and Marianne Kenny Research Scholar in Neurology
Post-ischemic cell death is still poorly understood and remains a severe clinical problem. We aim to identify and better characterize cellular responses to ischemic stroke on a molecular level and eventually harness this knowledge to improve the treatment of stroke and other neurological disorders.
Research Directions and Goals:
1. Post-ischemic post-translational protein modifications:
It has been long known that ischemic stroke leads to an immediate and prolonged shut-down of protein synthesis in affected brain cells. However, it has not been adequately acknowledged that, as a consequence, cells have to cope with the ischemic stress using the existing pre-ischemic protein pool. Protein modifications have the power to effectively change protein functions and stabilities, and thus hold promise as an important molecular modulator of ischemic cell fate. Therefore, a major research interest of our laboratory is A) to identify proteins that undergo modifications after ischemia, and B) investigate the impact of these modifications on ischemic cell fate.
Protein ubiquitination critically supports cell survival under stress conditions, such as heat-shock, irradiation, inflammation or oxidative stress. We have established that cerebral ischemia, which constitutes a major stress to brain cells, leads to a vast induction of protein ubiquitination (Hochrainer, Jackman et al, Stroke 2012; 43(8): 2229; Hochrainer et al, JCBFM 2015; 35(1): 1; Hochrainer, Transl Stroke Res 2018; 9(2): 157). Using mass-spectrometry we have identified proteins that are targeted by ubiquitination after ischemia. In current studies we are investigating the impact of post-ischemic ubiquitin-conjugation to selected substrate proteins.
2. Post-ischemic changes in protein solubility:
Apart from the ubiquitin-focused research we have also by mass spectrometry identified proteins that migrate from a soluble to insoluble state early after ischemia. Specifically, we find that proteins involved in RNA metabolism are distinctively enriched in inclusions after ischemia. Among these proteins are TDP43, FUS and hnRNPA1 (Kahl, Blanco et al, Sci Rep. 2018; 8(1): 2701), RNA-binding proteins also found in inclusions in ALS and frontotemporal dementia. Unlike in neurodegenerative diseases, in which insoluble protein inclusions are irreversibly formed over the course of decades and may be a sign of forthcoming cell death, their accumulation after ischemia appears to be rapid and transient. The role of RNA-binding proteins and their accumulation in the stress response after ischemic stroke is another research interest of our laboratory.
Our ischemia models include A) an in vivo mouse model of middle cerebral artery occlusion (MCAO), and B) in vitro ischemia models through oxygen and glucose deprivation of organotypic hippocampal slice cultures and primary mouse brain cells. We combine these models with cutting-edge molecular, cell biology and biochemical approaches to address the above raised questions.
Current Lab Members:
* Victoria Palfini, Research Technician
* Shanmukha Priya Srinivasan, Intern
* Carrie Poon, PostDoc (in collaboration with Anrather Laboratory)
* Gianfranco Racchumi, Research Specialist (in collaboration with Anrather Laboratory)
Past Lab Members:
* Ismary Blanco (8/2016-6/2018): Research Technician - now PhD student at Georgetown University
* Reunet Rodney-Sandy (8/2014-7/2016): Research Technician - now Laboratory Coordinator at Columbia University Irving Medical Center
* Shilpa Swaminathan (1/2018-6/2018): Intern from SASTRA University (India)
* Mohan Harihar Milaganur (1/2017-6/2017): Intern from SASTRA University (India) - now Masters student at the University of Michigan
* Nefertari Duversaint (6/2016-8/2016): Intern from CUNY
* Vaishali Balachandran (1/2016-6/2016), Intern from SASTRA University (India) - now Masters Student at Cornell University
* Habib Zahir (6/2015-8/2015): Intern from Hunter College - now Medical Student at the College of Osteopathic Medicine
* Juhi Baskar (1/2015-6/2015): Intern from SASTRA University (India) - now Lead Project Engineer at LVPEI Center for Innovation (India)
* Mehmet Kaplan (7/2013-9/2013): Intern from Ege University (Turkey) - now PhD student at the Medical University of Innsbruck (Austria)
* Victoria Olaseun (5/2013-8/2013): Intern from Lehman College
- Kahl A, Blanco I, Jackman K, Baskar J, Milaganur Mohan H, Rodney-Sandy R, Zhang S, Iadecola C and *#Hochrainer K. Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases. Sci Rep. 2018; 8(1): 2701. DOI:10.1038/s41598-018-21063-z. (*corresponding and #senior author).
- *#Hochrainer K. Protein modifications with ubiquitin as response to cerebral ischemia-reperfusion injury. Transl Stroke Res. 2018; 9(2): 157-173. (*corresponding and #senior author).
- *Hochrainer K, Pejanovic N, Olaseun VA, Zhang S, Iadecola C and Anrather J. The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation. Nucleic Acids Res. 2015; 43(20): 9889-904. (*corresponding author).
- *Hochrainer K, Jackman K, Benakis C, Anrather J and *Iadecola C. SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion. J Cereb Blood Flow Metab 2015; 35(1): 1-5. (*corresponding authors).
- Abe T, Zhou P, Jackman K, Capone C, Casolla B, Hochrainer K, Kahles T, Ross ME, Anrather J and Iadecola C: Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. Stroke 2013; 44(8): 2284-91.
- Hochrainer K, Racchumi G and Anrather J: Site-Specific phosphorylation of the p65 protein subunit mediates selective gene expression by differential NF-kB and RNA Polymerase II promoter recruitment. J Biol Chem 2013; 288(1): 285-93.
- Hochrainer K, Jackman K, Anrather J and Iadecola C. Reperfusion rather than ischemia drives the formation of ubiquitin aggregates in the mouse neocortex after middle cerebral artery occlusion. Stroke 2012; 43(8): 2229-2235.
- Hochrainer K, Racchumi G, Zhang S, Iadecola C and Anrather J: Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteolysis. Cell Mol Life Sci. 2012; 69(12): 2057–2073.
- Kunz A, Abe T, Hochrainer K, Shimamura M, Anrather J, Racchumi G, Zhou P and Iadecola C: Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion. J Neurosci. 2008; 28(7): 1649-1658.
- Hochrainer K, Racchumi G and Anrather J: Hypo-phosphorylation leads to nuclear retention of NF-kappaB p65 due to impaired IkappaBalpha gene synthesis. FEBS Lett. 2007; 581(28): 5493-5499.
National Institute of Neurological Disorders and Stroke
American Heart Association
Sackler Brain and Spine Institute
Feil Family Foundation
Presidents Council of Cornell Women
Costantino Iadecola (BMRI)
Josef Anrather (BMRI)
Ping Zhou (BMRI)
Ulrike Resch (Medical University of Vienna, Vienna, Austria)
Agnidipta Ghosh (Albert Einstein School of Medicine, NY, USA)