Manuel Buttini
Université du Luxembourg
Luxembourg
DJ-1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson's Disease
FNR
340,000
01/06/2013
3
Parkinson’s disease (PD) is a common chronic neurodegenerative disorder with major motor, but also a number of non-motor disease manifestations that significantly impair quality of life afflicted patients. 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. Since familial PD forms resemble sporadic PD forms in most disease manifestations, these genetic factors provide entry points for the study of molecular mechanisms of the disease. One such genetic factor is DJ-1. Loss-of-function mutations of DJ-1 are associated with recessive forms of familial PD. DJ-1 is a very multifaceted protein: in vitro studies have shown that it is ubiquitous, present in or near different cell compartments (cytosol, nucleus, mitochondria), binds to proteins as well as RNA, and is involved in mitochondrial maintenance, signal transduction, transcription regulation, and protection against oxidative stress. In vivo, deletion of DJ-1 exacerbates neuronal dysfunction and injury in response to MPTP or ischemic injury, and its administration or replacement is neuroprotective. However, which specific neurodegeneration pathways, among all the possible ones, are prevented by DJ-1 actions in vivo warrants further investigation. We therefore propose to use transgenic mouse models that model the chronic nature of PD-like neuronal dysfunction and injury, and cross them onto DJ-1 deficient mice. The two transgenic mouse lines express abnormal, pathogenic forms of alpha-synuclein and LRRK2, respectively, and their phenotype is reminiscent of early PD. Through the removal of DJ-1, we expect to unleash neurodegeneration that will induce a phenotype that is closer to full-blown PD. We have already generated and phenotyped ourselves all the mouse lines that we will use to generate the new models. We will analyse the new models behaviourally, neuropathologically, and, to characterize the neurodegeneration pathways, by a set of omics approaches. To characterize disease progression, we will do these analyses in at least two different age groups. We will subject the data to statistical evaluation and network reconstruction to identify potential new key players of disease initiation and progression, and assess their relevance by investigating their expression modulation in PD and control brain tissues.
https://www.fnr.lu/projects/dj-1-linked-neurodegeneration-pathways-in-new-mouse-models-of-parkinsons-disease-2/