DJ1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson s Disease

• Applicant: Professor Dr. Wolfgang Wurst
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 230746918

Parkinson s disease (PD) is a common, age-related chronic neurodegenerative disorder with major motor, but also a number of non-motor disease manifestations that significantly impair the quality of life of afflicted patients and impose a heavy socio-economic burden. Current treatments are symptomatic and can manage most motor symptoms, but there is no cure or disease-modifying therapy. It is therefore essential to gain more insight into PD-relevant neurodegeneration pathways in order to define novel therapeutic opportunities. Major advances have been achieved over the last decade in starting to uncover such pathways by the identification of genetic factors responsible for familial forms of the disease. One such genetic factor is DJ-1. Loss-of-function mutations of DJ-1 are associated with rare recessive forms of familial PD. In vivo, deletion of DJ-1 exacerbates neuronal dysfunction and death in response to MPTP or ischemic brain injury, and its administration or replacement is neuroprotective. To study these pathways, we propose to use genetic mouse models of PD that model specifically neuronal dysfunction and cross them onto DJ-1 deficient mice. The two mouse lines with a PD-relevant phenotype express abnormal, pathogenic forms of alpha-synuclein and LRRK2, respectively, but their phenotype is mild and reminiscent of early or pre-symptomatic PD. Through the removal of DJ-1 in these two models, we expect to unleash neurodegeneration that will induce a phenotype closer to full-blown PD. We will analyze the new models behaviourally, neuropathologically, and, to characterize the neurodegeneration pathways, by a set of omics/systems approaches. To characterize disease progression, we will do these analyses in different age groups: before disease onset, and at peak disease manifestation. We will subject the data to statistical evaluation and network reconstruction to identify potential new key players of disease initiation and progression.

• DFG Programme: Research Grants
• International Connection: Luxembourg
• Participating Person: Dr. Manuel Buttini