Genetic Dysregulation

Direct changes to the genetic coding sequence can result in altered protein function and behavior, such as the pathogenic mutations identified in the PD-associated gene LRRK2. However, dysregulation of the mechanisms that control gene expression and protein synthesis can dictate how much or little of a protein is ultimately made in a cell and may also be a risk or pathogenic factor for PD. These mechanisms can include sequence alterations to DNA regulatory regions or multiplication of gene copy, such as those found in the gene for alpha-synuclein. Alterations to transcription factors that control dopamine neuron characteristics, such as Pitx3, Engrailed and Nurr1, have also been linked to PD (Flames and Hobert, 2009; Le et al., 2009; Haubenberger et al., 2009; Xu et al., 2009).

Epigenetic changes (those not due to direct DNA sequence variation) and RNA interference mechanisms (such as microRNA) can also control the amount of protein generated, suggesting the possibility of additional pathogenic mechanisms.