The paths to neurodegeneration in genetic Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, which results from the loss of specific population of neurons, namely the pigmented dopamine secreting neurons of the substnatia nigra pars compatica (SNPc) of midbrain. The exact cause leading to nigrostriatal cell death is not yet known. In recent years, accumulating evidence from the identified molecular events in familial forms of PD contributed much to unraveling the mechanisms by which dopaminergic neurons die in PD and which hopefully would lead to the development of therapeutic interventions. Several major disease causing pathways were identified so far. These are possibly interconnected and some genes share a common pathway e.g., (i) defects in ubiquitin-proteasome pathway and protein misfolding and aggregation caused by α-synuclein and Parkin gene defects; (ii) defects in mitochondrial morphology and function in PINK1/Parkin and DJ-1 mutations; (iii) increased susceptibility to cellular oxidative stress which appear to underlie defects in α-synuclein, Parkin and DJ-1 genes. The aim of this review is to shed light on the molecular mechanisms by which mutations in familial-linked genes cause PD.