Genetic Insights into the Molecular Pathophysiology of Depression in Parkinson's Disease.

: Parkinson's disease (PD) is a clinically heterogeneous disorder with poorly understood pathological contributing factors. Depression presents one of the most frequent non-motor PD manifestations, and several genetic polymorphisms have been suggested that could affect the depression risk in PD. Therefore, in this review we have collected recent studies addressing the role of genetic factors in the development of depression in PD, aiming to gain insights into its molecular pathobiology and enable the future development of targeted and effective treatment strategies. : we have searched PubMed and Scopus databases for peer-reviewed research articles published in English (pre-clinical and clinical studies as well as relevant reviews and meta-analyses) investigating the genetic architecture and pathophysiology of PD depression. : in particular, polymorphisms in genes related to the serotoninergic pathway (sodium-dependent serotonin transporter gene, , tryptophan hydrolase-2 gene, ), dopamine metabolism and neurotransmission (dopamine receptor D3 gene, , aldehyde dehydrogenase 2 gene, , neurotrophic factors (brain-derived neurotrophic factor gene, ), endocannabinoid system (cannabinoid receptor gene, CNR1), circadian rhythm (thyrotroph embryonic factor gene, ), the sodium-dependent neutral amino acid transporter B(0)AT2 gene, ), and genetic locus were detected as altering susceptibility to depression among PD patients. However, polymorphisms in the dopamine transporter gene (), monoamine oxidase A () and B () genes, catechol-O-methyltransferase gene (), , and have not been related to PD depression. : the specific mechanisms underlying the potential role of genetic diversity in PD depression are still under investigation, however, there is evidence that they may involve neurotransmitter imbalance, mitochondrial impairment, oxidative stress, and neuroinflammation, as well as the dysregulation of neurotrophic factors and their downstream signaling pathways.