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See detailAbsence of regulator of G-protein signaling 4 does not protect against dopamine neuron dysfunction and injury in the mouse 6-hydroxydopamine lesion model of Parkinson's disease
Ashrafi, Amer UL; Garcia, Pierre UL; Kollmus, Heike et al

in Neurobiology of Aging (2017), 58

Regulator of G-Protein Signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy ... [more ▼]

Regulator of G-Protein Signaling 4 (RGS4), a member of the RGS family of proteins that inactivate G-proteins, has gained interest as a potential drug target for neurological disorders, such as epilepsy and Parkinson’s disease (PD). In the case of PD, the main current option for alleviating motor symptoms are dopamine replacement therapies, which have limitations because of side effects, and reduced effectiveness over the long term. Research on new non-dopaminergic PD drug targets has indicated that inhibition of RGS4 could be an effective adjuvant treatment option. The effectiveness of RGS4 inhibition for an array of PD-linked functional and structural neuroprotection endpoints has not yet been demonstrated. Here, we use the 6-Hydroxydopamine (6-OHDA) lesioning model of the nigrostriatal pathway in mice to address this question. We observe, using a battery of behavioral and pathological measures, that mice deficient for RGS4 are not protected from 6-OHDA induced injury, and show 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. [less ▲]

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See detailParkinson's disease: Evaluation of a neuroprotective target and identification of candidate biomarker signatures using murine models
Ashrafi, Amer UL

Doctoral thesis (2017)

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 ... [more ▼]

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. [less ▲]

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