Doctoral thesis (Dissertations and theses)
Parkinson's disease: Evaluation of a neuroprotective target and identification of candidate biomarker signatures using murine models
Ashrafi, Amer
2017
 

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Keywords :
Parkinson's disease; RGS4; Biomarker
Abstract :
[en] Parkinson's disease (PD) is one of the most common age-related neurologic diseases. While existing therapeutic approaches, focusing on dopamine replacement, can alleviate some of the cardinal symptoms, they are associated with severe adverse effects in the long-term. Therefore, identification of new therapeutic interventions to reverse, stop or slow down the progression of Parkinson’s disease is a major focus of PD research. Similarly, identifying reliable biomarkers that would enable early therapeutic intervention is another key area of current research. Here, we evaluated a recently proposed non-dopaminergic protein drug target for PD, Regulator of G-Protein Signaling 4 (RGS4), and performed preliminary studies aimed at the identification of novel biomarker signatures using two murine models of Parkinson’s disease. Recent research on new non-dopaminergic PD drug targets has indicated that inhibition of RGS4, a member of the RGS family of proteins that inactivate G-proteins, could be an effective adjuvant treatment option. However, the effectiveness of RGS4 inhibition for an array of PDlinked functional and structural neuroprotection endpoints had not yet been demonstrated. Here, we used the 6-Hydroxydopamine (6-OHDA) lesioning mouse model to address this question. We observed, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA induced injury, and showed enhanced susceptibility in some measures of motor function. Our results suggest that inhibition of RGS4 as a non-dopaminergic target for PD should be approached with caution. In the second part of this study, two alpha-synuclein based PD mouse models, human E46K mutated overexpressed alpha-synuclein and alpha-synuclein fibril spreading models, were used to investigate early pathological events in PD and identify novel candidate biomarker signatures for subsequent validation. Two different time points, before disease onset, and at peak disease manifestation, were analyzed in the two models. Using multiple histopathology and molecular biology techniques, we were able to identify complex changes in patterns of gene expression at early stages of the disease, well before neurodegeneration is detectable. These findings might open venues for new therapeutic strategies and provide insights on the molecular perturbations occurring during the earliest stages of the disease, paving the way for the development of a biomarker signatures for early diagnosis of Parkinson’s disease.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
Disciplines :
Biochemistry, biophysics & molecular biology
Biotechnology
Author, co-author :
Ashrafi, Amer ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Language :
English
Title :
Parkinson's disease: Evaluation of a neuroprotective target and identification of candidate biomarker signatures using murine models
Defense date :
29 June 2017
Number of pages :
xviii, 124 + 4
Institution :
Unilu - University of Luxembourg, Esch-sur-Alzette, Luxembourg
Degree :
Docteur en Biologie
Jury member :
Michelucci, Alessandro 
Giesert, Florian
Focus Area :
Systems Biomedicine
Funders :
FNR - Fonds National de la Recherche [LU]
Available on ORBilu :
since 18 July 2017

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