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

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite intense research, the specific molecular events underlying this disease are still unknown. The lack of suitable vertebrate models of the disease likely represents the greatest unmet need in the field, and the overriding goal of this project is to take a novel approach in generating a mouse model of PD. We will take immediate advantage of the recent discovery of a mitochondrial deficiency disorder with significant pathological overlap with PD. A nuclear encoded mitochondrial chaperone is critical for the assembly of the ~45 Complex-1 subunits and their function, and is unequivocally associated with a genetic mitochondrial and neuropathological disease in humans. During the project, we will characterize the first conditional knockout mouse targeting Complex-1 of the electron transport chain, implicated in PD etiology at many levels. We will place a particular emphasis on the patterns of neurodegeneration observed, and for the appearance of proteinacious inclusions, such as alpha-synuclein and/or ubiquitin inclusions. In addition, two-hit models may be explored. The resources generated during the project may provide ground-breaking vertebrate models to study PD, addressing a significant void in the field. This work will directly evaluate a major hypothesis in the study of PD, and may elucidate still unknown molecular mechanisms of PD and energy deficiency diseases, perhaps leading to innovative therapeutic strategies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Matthew J. LaVoie, Ph.D.