Parkinson's disease: Evaluation of a neuroprotective target and identification of candidate biomarker signatures using murine models

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.