Targeting mitochondrial Complex-1 to establish and study innovative models of Parkinson's disease

• Applicant: Dr. Julia Schlehe
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2009 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 140085815

• Final Report Year: 2012

Final Report Abstract

Mitochondria are a major source of energy for every cell, by providing the molecule ATP through a series of chemical reactions called the respiratory chain. The first enzyme in the respiratory chain is called Complex-1. Defects in Complex-1 can lead to energy deficiency and oxidative stress within the cell, and are the most common cause of mitochondrial disease, such as Leigh syndrome, LHON or MELAS, and are also involved in Parkinson’s disease, the second most common neurodegenerative disease. We studied the effects of a specific defect that disturbs the assembly of Complex-1, and which was first described in a series of patients suffering from a juvenile onset, and ultimately fatal, mitochondrial disease that primarily involved the death of nerve cells. We established a cell culture and an animal model for this defect, and found an increase in oxidative stress due to mitochondrial defects. The cells were growing slower, and showed damaged mitochondrial DNA, which is a common finding in mitochondrial and Parkinson’s disease. Our novel mouse model will allow us to analyze the progression of degeneration, and to study features specific for nerve cells, called axons. By understanding the balance between nerve cell survival and death, we and other researchers will be able to develop future therapeutic strategies.

Publications

• PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell, 2011 Nov 11; 147(4): 893-906
  Wang X., Winter D., Ashrafi G., Schlehe J., Wong Y.L., Selkoe D., Rice S., Steen J., LaVoie M.J., Schwarz T.L.
  
• “Exploring the pathological consequences of failed mitochondrial Complex-1 assembly”. Neuroscience, Washington DC. November 12-16, 2011. Abstract No. 885
  Schlehe J., Labunska T., Journel M., LaVoie M.J.
  
• “Pathological consequences of mitochondrial Complex-1 misassembly in vitro and in vivo”, Keystone Symposium Mitochondrial Dynamics and Function, Banff, March 19-24, 2012. Abstract No. 312
  Schlehe J., Journel M., Taylor K., LaVoie M.J.