New Molecular Avenues in Parkinson ’ s Disease Therapy

Mario      Di Napoli

doi:10.2174/156802609789378254

Abstract

Idiopathic Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The degeneration of dopamine and other neuronal populations in PD lead to both chronic motor and non-motor disabilities but the mechanisms remain unclear. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, supporting a major role for (i) protein aggregation and neurotoxic α-synuclein oligomeric species due to an altered protein quality control, (ii) parkin-driven deregulation of the ubiquitin-proteasome system, (iii) oxidative stress and mithocondrial dysfunction, and, finally, (iv) disturbed kinase activity. The elucidation of these new molecular pathways has increased our knowledge of PD pathophysiology, but it remains an open question whether alterations of these pathways lead to different entities of PD or whether they finally converge at a point that is the common pathogenetic denominator of PD. However, the knowledge of validated targets is in its infancy, and thus, traditional target-based drug discovery strategies are of limited use. Alternative approaches are needed, and early attempts were aimed at identifying molecules inhibiting the aggregation of α-synuclein fragments, interfering with the ubiquitin proteasome pathway and reducing oxidative stress. Such discovery strategies have an impact on the configuration of screening cascades for effective translation of drug candidates toward clinical trials. This review examines how these genetic findings provided us with suitable animal models and how the gained insights will contribute to better therapies for PD.

Keywords: Parkinson's disease, ubiquitin-proteasome system, parkin, autophagy, α-Synuclein, UCH-L1 (ubiquitin carboxyterminal hydrolase L1), DJ-1, Pink1 (PTEN-induced kinase 1), Leucine-rich repeat kinase 2 (LRRK2), Dopaminergic neurons