On the roles of genes in Parkinson's disease

Parkinson’s 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’s disease pathology, we investigated genes which are involved in protein aggregation and the ubiquitin‐proteasome system (α‐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’s 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‐/‐; α‐synuclein over expressing and α‐synuclein‐/‐; Darpp‐32‐/‐ and Darpp‐32 T34A mutant and MitoPark mice and in 6‐OHDA treated rats). A possible co‐regulation between Lrrk2 and α‐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’s 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’s disease.

List of scientific papers

I. Westerlund M, Galter D, Carmine A, Olson L (2005). Tissue- and species-specific expression patterns of class I, III, and IV Adh and Aldh 1 mRNAs in rodent embryos. Cell Tissue Res. 322(2): 227-36. Epub 2005 Nov 3
https://pubmed.ncbi.nlm.nih.gov/16047160

II. Westerlund M, Belin AC, Felder MR, Olson L, Galter D (2007). High and complementary expression patterns of alcohol and aldehyde dehydrogenases in the gastrointestinal tract: implications for Parkinsons disease. FEBS J. 274(5): 1212-23. Epub 2007 Jan 25
https://pubmed.ncbi.nlm.nih.gov/17257171

III. Carmine Belin A, Westerlund M, Anvret A, Lindqvist E, Pernold K, Ögren S O, Duester G, Galter D (2008). Modeling Parkinsons disease genetics: altered function of the dopamine system in Adh4 knockout mice. [Submitted]

IV. Westerlund M, Carmine Belin A, Olson L, Galter D (2008). Cellular localization of multi‐drug resistance 1 (MDR1) in human and rodent nervous system and peripheral organs. [Submitted]

V. Westerlund M, Carmine Belin A, Anvret A, Håkansson A, Nissbrandt H, Lind C, Sydow O, Olson L, Galter D (2008). Association of a multi‐drug resistance 1 polymorphism with Parkinsons disease. [Submitted]

VI. Westerlund M, Carmine Belin A, Anvret A, Håkansson A, Nissbrandt H, Lind C, Sydow O, Olson L, Galter D (2008). Cerebellar alpha‐synuclein levels are decreased in Parkinsons disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. [Submitted]

VII. Westerlund M, Belin AC, Anvret A, Bickford P, Olson L, Galter D (2008). Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: Implications for Parkinsons disease. Neuroscience. 152(2): 429-36. Epub 2008 Jan 10
https://pubmed.ncbi.nlm.nih.gov/18272292

VIII. Galter D, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L (2006). LRRK2 expression linked to dopamine-innervated areas. Ann Neurol. 59(4): 714-9
https://pubmed.ncbi.nlm.nih.gov/16532471

IX. Carmine Belin A, Westerlund M, Sydow O, Lundströmer K, Håkansson A, Nissbrandt H, Olson L, Galter D (2006). Leucine-rich repeat kinase 2 (LRRK2) mutations in a Swedish Parkinson cohort and a healthy nonagenarian. Mov Disord. 21(10): 1731-4
https://pubmed.ncbi.nlm.nih.gov/16817197

X. Westerlund M, Ran C, Borgkvist A, Sterky FH, Lindqvist E, Lundströmer K, Pernold K, Brené S, Kallunki P, Fisone G, Greengard P, Larsson N‐G, Olson L, Galter D (2008). Leucine‐rich repeat kinase 2 and other PARK genes in rodent models of Parkinsons disease. [Submitted]

XI. Galter D, Westerlund M, Belin AC, Olson L (2007). DJ-1 and UCH-L1 gene activity patterns in the brains of controls, Parkinson and schizophrenia patients and in rodents. Physiol Behav. 92(1-2): 46-53. Epub 2007 May 23
https://pubmed.ncbi.nlm.nih.gov/17599367

XII. Carmine Belin A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O, Galter D (2007). S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinsons disease in Sweden. Parkinsonism Relat Disord. 13(5): 295-8. Epub 2007 Feb 6
https://pubmed.ncbi.nlm.nih.gov/17287139