Funded Studies
Objective/Rationale:
A partial deficit in the level of Ran-binding protein-2 (RanBP2) confers neuroprotection to neurons upon aging and deleterious stimuli promoting oxidative stress, a stress condition linked also to the dysfunction of dopaminergic neurons and Parkinson’s disease. Hence, this proposal aims to assess the neuroprotective role of RanBP2 in the loss of dopaminergic neurons in an experimental model of Parkinson's.
Project Description:
The neurotoxic compound, MPTP, is up-taken selectively by dopaminergic neurons, promotes oxidative stress and causes the progressive degeneration of these neurons. These effects closely recapitulate features observed with various forms of Parkinson’s disease. Hence, we will administer MPTP to two groups of mice with normal and reduced levels of RanBP2, and compare the effects of RanBP2 in protecting dopaminergic neurons against MPTP-induced neurodegeneration and other features linked to Parkinson's.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Support of a role of the multifunctional protein, RanBP2, in the neuroprotection of dopaminergic neurons and in delaying cardinal features and symptoms invariably associated with Parkinson’s disease will open new venues to diagnose and treat Parkinson's by i) helping to define physiological and biological processes linked to RanBP2 in Parkinson’s disease and ii) establishing RanBP2 and allied biological processes as novel therapeutic targets.
Anticipated Outcome:
The anticipated outcome from these studies is the demonstration of a role of RanBP2 in the modulation of the expression of hallmark features associated with Parkinson’s disease. Such an outcome will provide us with additional and valuable tools to understand the molecular pathogenesis of Parkinson’s disease and establish novel therapeutic targets to delay the onset and progression of clinical and pathological features associated with Parkinson's.
Final Outcome
Our project sought to explore the role of insufficiency of RAN-binding protein-2 (RANBP2) in modulating the expression of molecular, cellular and clinical manifestations associated with dopaminergic neurons and PD in an experimental model of the disease.
To this end, we found that insufficiency of RANBP2 increases the susceptibility of experimental models to chemically induced deficits in locomotor activity without apparently affecting the viability of dopaminergic neurons of various brain regions. These deficits are caused likely by changes in the levels of specific CNS metabolites, whose identification is currently underway.
On the other hand, insufficiency of RANBP2 has distinct effects on dopaminergic neurons of the neuroretina as reflected by the modulation of their numbers in the retina. Hence, RANBP2 emerges as a gene, whose functions modulate manifestations linked to dopaminergic neuronal functions and Parkinsonism.