Candidate genes for Parkinson disease: Lessons from pathogenesis

• The genetics of PD is complex, with several causative genes and risk factors.
• Mutations in known genes account for a minority of PD familial cases.
• Most proteins mutated in PD converge on processes that maintain cellular homeostasis.
• Dysfunctions in few essential and interconnected pathways trigger neuronal death.
• Impaired clearance systems, mitochondrial damage, ER stress and inflammation occur in PD.

Parkinson disease (PD) is a multifactorial neurodegenerative disease characterized by the progressive loss of specific neuronal populations and accumulation of Lewy bodies in the brain, leading to motor and non-motor symptoms. In a small subset of patients, PD is dominantly or recessively inherited, while a number of susceptibility genetic loci have been identified through genome wide association studies. The discovery of genes mutated in PD and functional studies on their protein products have provided new insights into the molecular events leading to neurodegeneration, suggesting that few interconnected molecular pathways may be deranged in all forms of PD, triggering neuronal loss. Here, we summarize the most relevant findings implicating the main PD-related proteins in biological processes such as mitochondrial dysfunction, misfolded protein damage, alteration of cellular clearance systems, abnormal calcium handling and altered inflammatory response, which represent key targets for neuroprotection.