On the roles of genes in Parkinson's disease

Abstract: Parkinson fs disease is a progressive neurodegenerative disorder which affects 1% of the population over the age of 60. In order to identify candidate genes with a potential role in Parkinson fs disease pathology, we investigated genes which are involved in protein aggregation and the ubiquitin ]proteasome system (alpha ]synuclein and ubiquitin carboxy ]terminal hydrolase L1, UCH ]L1), oxidative stress (DJ ]1), mitochondrial function (mitochondrial transcription factor A, TFAM), regulation of drug/toxin levels (multi ]drug resistance 1, MDR1 and alcohol and aldehyde dehydrogenases, ADH and ALDHs), as well as a gene with unknown function, but highly implicated in Parkinson fs disease genetics (leucine ]rich repeat kinase 2, LRRK2). (1) Using in situ hybridization, we characterized the cellular localization of candidate genes in both human and rodent tissues and found marked diversity in terms of areas and intensities of transcriptional activity. Some genes exhibited a widespread neuronal expression (UCH ]L1, DJ ]1, SNCA), one showed a particularly high expression in the dopamine target area striatum (LRRK2), some were expressed also in non ]neuronal tissues (LRRK2, DJ ]1, MDR1), and others exclusively so (ADH1, ADH4). (2) We also searched for genetic variability in a Swedish case ]control sample consisting of 310 Parkinson patients and 315 controls, which resulted in identification of several potential risk factors (LRRK2 G2019S; MDR1 1236C/T; SNCA rs2737029 (A/G) and rs356204 (A/G), as well as protective factors (UCH ]L1 S18Y) for disease. (3) Behavior, gene expression and/or brain neurotransmitter levels were studied in different transgenic and drug ]induced rodent models (Adh4 ]/ ]; alpha ]synuclein over expressing and alpha ]synuclein ]/ ]; Darpp ]32 ]/ ] and Darpp ]32 T34A mutant and MitoPark mice and in 6 ]OHDA treated rats). A possible co ]regulation between Lrrk2 and alpha ]synuclein gene activities was found. Moreover, Adh4 ]/ ] mice displayed alterations in substantia nigra dopamine levels, as well as in dopamine ]related behavior. In conclusion, the findings in the present thesis suggest an important role for genetic risk factors in the pathogenesis of Parkinson fs disease. Due to the great complexity of the disease, it seems likely that several molecular pathways and networks involving different genes and downstream effectors can affect the trophic support and/or survival of dopamine neurons, subsequently leading to Parkinson fs disease.