PROBLEM STATEMENT
Parkinson disease (PD) is the second most common neurodegenerative disease in populations aged 60 years or above. Current estimates indicate that the clinically diagnosed PD affects more than 6 million people worldwide, and presents a significant socio-economic burden. While the underlying cause of PD remains a matter of rigorous scientific inquiry, examination of (post-mortem, deceased) patient brains shows that there is a profound loss of dopamine producing neurons in several brain regions, particularly affecting a region in midbrain called the substantia nigra (pars compacta). Based on these observations, the clinical interventions are aimed at symptomatic relief, with dopamine replacement (through L-dopa treatment) as the gold-standard approach. However, the disease is progressive and eventually current clinical therapies lose efficacy in majority of the patients after 5-10 years. Hence, there is a dire need for disease modifying treatments that address the underlying factors initiating and contributing to the loss of neurons in PD brain. In this regard, genetic findings in rare inherited forms of PD and histopathological observations incriminate abnormal behavior of a neuronal protein called alpha-synuclein (aSyn). The physiological function(s) of this protein remains elusive; however, under disease states, this protein forms clumps (technically: misfolded aggregates) which deposit in the nervous system and impact the normal function of neurons. Moreover, once misfolded, the putative pathogenic forms of aSyn propagate within the affected network of neurons, further compromising their function and progressive involvement of additional brain regions. Hence, modulating the factors that may promote pathological aSyn misfolding, blocking the propagation of misfolded aSyn in neuronal networks and augmenting cytoprotective response towards mitigating neuronal toxicity represent promising targets in PD therapy, and are actively being pursued in preclinical research and in clinical trials. Hence, as part of the research project , the studies described below were carried out as a contribution to discovery of disease mechanisms, and translational scientific inquiry into the potential utility of viral mediated gene delivery/gene modification in PD.
SOCIETAL IMPACT
Research into mechanisms of neuronal dysfunction caused by aSyn and establishing preclinical research paradigms to modulate aSyn neurotoxicity are needed for better understanding PD and related diseases.
OVERALL OBJECTIVES
Therefore, the overall objectives of the project were to: i) modulate the expression levels of neuronal aSyn to prevent its misfolding, ii) study the mechanisms that render neurons vulnerable to the toxicity by misfolded aSyn, and iii) provide proof-of-concept (PoC) preclinical evidence regarding the utility of gene modulation using viral vectors.
