Research

  Summary  

Hans Bueler was trained as a molecular biologist and neuroscientist at the University of Zurich in Switzerland, where he received a M.S. degree in 1988 and Ph.D. in 1992. During his doctoral thesis he developed the first prion protein (PrP)-deficient mice and showed that they were resistant to contracting prion disease and failed to replicate the infectious agent. This seminal finding established that PrP is essential for prion disease pathogenesis and prion propagation. After postdoctoral research at the Whitehead Institute for Biomedical Research and Harvard Medical School in Boston in tumor immunotherapy, Dr. Bueler started his own lab back at the University of Zurich as an Assistant Professor of the Swiss National Science Foundation, focusing on the development of viral vectors for gene therapyof Parkinson’s disease and amyotrophic laterals sclerosis. His group demonstrated that AAV-mediated overexpression of the chaperone Hsp70 and the recessive Parkinson’s disease-linked proteins DJ-1 and Parkin confer protection against dopaminergic system degeneration in a mouse model of sporadic Parkinson’s disease. As an Associate Professor at the University of Kentucky Dr. Bueler studied the mechanisms of neuronal dysfunction in animal models of familial Parkinson’s disease. His lab has generated mice lacking PTEN-induced kinase 1 (PINK1), a mitochondrial kinase linked to recessive inherited Parkinson’s disease. PINK1 plays an important role in mitochondrial quality control by regulating the selective degradation of depolarized mitochondria through mitophagy. Loss of PINK1 in mice leads to mitochondrial abnormalities, oxidative stress, alterations in autophagy/mitophagy, defects in Akt cell survival signaling and abnormalities in neurogenesis. These mechanisms in conjunction with other stress factors may be involved in neurodegeneration and neuropsychiatric disorders. Current projects in the lab investigate the importance of PINK1 and mitochondrial function/dynamics in neural stem biology/neurogenesis, astrocyte physiology and in the formation of tumors.Dr. Bueler has joined the School of Life Sciences and Technology of the Harbin Institute of Technology in October 2013.

  

 Education

  

  • Studies in Biology, University of Zurich, Switzerland, 1983-1988

  • M.Sc. in Molecular Biology, University of Zurich, 1987-1988

  • Ph.D. in Molecular Biology/Neuroscience, University of Zurich, 1989-1992

     

  Positions

 

  • Postdoc - Institute of Molecular Life Sciences (formerly Molecular Biology), University of Zurich, Switzerland, 1992-1993

  • Postdoctoral Fellow - Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, 1993-1996

  • Assistant Professor (START Fellow) - Institute of Molecular Life Sciences, University of Zurich, Switzerland, 1996-2006

  • Associate Professor – Department of Anatomy and Neurobiology, University of Kentucky, Lexington, 2006-2013

  • Professor - School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China, since October 2013

      

  Research Interests

 

  • Molecular genetics and cellular mechanisms of neurodegeneration in Parkinson’s disease and related neurodegenerative disorders

  • Development of cell-based assays to screen small molecules, drugs and natural compounds with the potential to block neuronal loss

  • Importance of PINK1-regulated mitochondrial quality control and mitochondrial dynamics in neurodegeneration, neurogenesis and tumorigenesis

  • Viral gene transfer (AAV, retroviruses, lentiviruses) forin vivo gene therapy and to study basics science-related questions

      

    Molecular Mechanisms and Genetics of Parkinson’s disease (PD)  

     

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

  

    Recent review on PD genetics:Ryan et al.,015: Trends in Biochemical Sciences 40, 200-210.

 

    Techniques and Tools in the Lab

  

  • Generation of knockout/transgenic mice

  • Wide range of molecular biology, cell biology and biochemistry methods

  • Culture and genetic modification of primary cells (MEFs, astrocytes, neurons, stem cells)

  • Isolation of hippocampal neural stem cells, characterization of adult neurogenesis in the hippocampus of mice

  • Tissue sectioning, immunohistochemistry, histology

  • 3D image generation and analysis (Vaa3D)

  • Production and purification of recombinant AAV, retroviruses and lentiviruses, viral gene transfer to the brain and primary cells

  • Stereotaxic surgery

  • Light, confocal and electron microscopy

  • Isolation and purification of mitochondria

  • Real-time measurements of mitochondrial respiration and glycolysis in living cells and with isolated mitochondria (Seahorse Flux Analyzer)

     

  Selected Publications

             

Sandeep Kumar Agnihotri, Ruifang Shen,Jihong Li,Xu Gao and Hansruedi Büeler (2017).Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus. FASEB J publication. March 21,2017, doi: 10.1096/fj.201600960RR

Triplett, J.C., Zhang, Z., Sultana, R., Cai, J., Klein, J.B., Bueler, H., Butterfield, D.A. (2015). Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice: insights into mechanisms of familial Parkinson’s disease. J Neurochem. 133, 750-765.

Sanchez, G., Varaschin, R.K., Bueler, H., Marcogliese, P.C., Park, D.S., and Trudeau, L.E. (2014). Unimpaired striatal dopamine release in juvenile Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice. PLOS One 9, e94826.

Shridas, P., Zhi, L., Akundi R.S., Webb, N.R., Pearson, K.J. and Bueler, H. (2013). PTEN-induced kinase 1 regulates mitochondrial integrity and insulin secretion in mouse pancreatic b-cells, J Endocrinology Diabetes Obes 1 (1), 1007

Ellis, G.I., Zhi, L., Akundi, R.S., Bueler, H. and Marti, F (2013). Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T cell development and function. Eur. J. Immunol. 43, 3355-3360.  

Wang, R., Li, J.J., Diao, S., Kwak, Y-D., Liu, L., Zhi, L., Bueler, H., Bhat, N.R., Williams, R., Park, E.A. and Liao, F.F. (2013). Metabolic stress modulates Alzheimer's b-secretase gene transcription via SIRT1-PPARg-PGC1 in neurons, Cell Metabolism 17, 685-694.  

Akundi, R.S., Zhi, L., Sullivan, P. G. and Bueler, H (2013). Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice, Neurodegener Dis12, 136-149. 

Akundi, R. S., Zhi, L. and Bueler, H. (2012). PINK1 enhances insulin-like growth factor-1-dependent Akt signaling and protection against apoptosis, Neurobiol Dis 45, 469-478.  

Akundi, R. S., Huang, Z., Eason, J., Pandya, J. D., Zhi, L., Cass, W. A., Sullivan, P. G. and Bueler, H. (2011). Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLOS One 6, e16038.   

Saini, N., Oelhafen, S., Hua, H., Georgiev, O., Schaffner, W. and Bueler, H. (2010). Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways. Neurobiol Dis 40, 82-92.   

Bueler, H. (2009). Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease.Exp Neurol, 218, 235-246 (Special Issue: Mitochondria and Neurodegeneration).  

Paterna, J.C., Leng, A., Weber, E., Feldon, J. and Bueler, H. (2007). DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice. Mol Ther, 15, 698-704.   

Dong, Z., Wolfer, D.P., Lipp, H.P. and Bueler, H. (2005). Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther, 11, 80-88.  

Paterna, J.C., Feldon, J. and Bueler, H. (2004). Transduction profiles of recombinant adeno-associated virus vectors derived from serotypes 2 and 5 in the nigrostriatal system of rats. J Virol, 78, 6808-6817.   

Dong, Z., Ferger, B., Paterna, J.C., Vogel, D., Furler, S., Osinde, M., Feldon, J. and Bueler, H. (2003). Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A, 100, 12438-12443.   

Furler, S., Paterna, J.C., Weibel, M. and Bueler, H. (2001). Recombinant AAV vectors containing the foot and mouth disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons. Gene Ther, 8, 864-873.   

Paterna, J.C., Moccetti, T., Mura, A., Feldon, J. and Bueler, H. (2000). Influence of promoter and WHV post-transcriptional regulatory element on AAV-mediated transgene expression in the rat brain. Gene Ther, 7, 1304-1311.  

Klein, C., Bueler, H. and Mulligan, R.C. (2000). Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines. J Exp Med, 191, 1699-1708.  

Glatzel, M., Flechsig, E., Navarro, B., Klein, M.A., Paterna, J.C., Bueler, H. and Aguzzi, A. (2000). Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci U S A, 97, 442-447.   

Azzouz, M., Hottinger, A., Paterna, J.C., Zurn, A.D., Aebischer, P. and Bueler, H. (2000). Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. Hum Mol Genet, 9, 803-811.   

Bueler, H., Aguzzi, A., Sailer, A., Greiner, R.A., Autenried, P., Aguet, M. and Weissmann, C. (1993). Mice devoid ofPrP are resistant to scrapie. Cell, 73, 1339-1347.   

Bueler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H.P., DeArmond, S.J., Prusiner, S.B., Aguet, M. andWeissmann, C. (1992). Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature, 356, 577-582.