Research
Neuro Science&Neurodegeneration
Publisher:喻庆勇  Time2016-12-23 View:15

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


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.


Research Team (first name/last name)

Lectuerer:         Fengtong Han Ph.D

Postdocs:           Sandeep Agnihotri, Ph.D.

PhD Students:     Liuke Sun, M.S. (March 2015)

Master Students:  Shuohai Zhang, Fei Wang

Technicians:       Ruifang Shen, M.S