Genes Linked to Parkinson Disease
Specific Gene Mutations May Point to Important Pathways in PD
Nov 11, 2009
Parkinson disease (PD) is one of the most frequently occurring neurodegenerative disorders. PD and its associated symptoms occur because of the death of a significant percentage of the specialized neurons located in a region of the brain known as the substantia nigra. The loss of these neurons leads to problems with movement initiation and regulation. This is manifested in patients by the occurrence of tremors and difficulty with muscular rigidity. Several gene mutations have now been linked to PD.
Inherited Forms of Parkinson Disease
While the majority of cases of PD appear to occur spontaneously, what is referred to as “sporadic” disease, there are instances where PD can be passed on genetically in an affected family. As is the case for many inherited disorders, there are two types of inherited PD, so-called “autosomal dominant” and “autosomal recessive”.
Human cells maintain two copies of each of their chromosomes and thus two copies, or alleles (pronounced ah-leels), of each gene. In disorders where the presence of one defective copy of a single gene can cause disease it is said to be dominant, conversely when a mutation must be present in both alleles of a gene in order to cause disease it is referred to as recessive.
In the genetics of human diseases, some genes are identified as increasing the chances of developing a disorder but are not directly causally related to the appearance of the disease, these genes are described as “risk factors.” In these cases you might have increased risk for developing the disease but never actually develop it. Where a mutation in a gene directly leads to the development of the disease, the mutation is said to be disease-causing.
Genes That Cause Parkinson Disease
Several genes have now been implicated in hereditary forms of this disorder. Understanding the function of these genes is helping researchers to identify what things go wrong not only in inherited forms of this disease but also in non-inherited (or sporadic) forms. Using genetic mapping studies, a list of genes, not surprisingly originally numbered according to the order in which they were discovered, have been associated with developing PD.
PARK-1 – also known as alpha-synuclein
PARK-2 – also known as Parkin
PARK-3 – gene region localized but exact identity remains unknown
PARK-4 – also related to alpha-synuclein as PARK-1 above but involves duplication of the gene
PARK-5 – also known as ubiquitin C-terminal hydrolase L1 (UCH-L1)
PARK-6 – also known as ‘PINK-1’ for PTEN-induced putative kinase 1
PARK-7 – also known as DJ-1
PARK-8 – also known as Leucine-rich repeat kinase 2; LRRK2 and known as dardarin
PARK-9 – also known as ATPase, type 13A2
Studies of the proteins produced by these various genes have begun to suggest that alterations in certain cellular functions may be important to the development of Parkinson disease. More importantly, continuing research links some of the different genes to being active in the same pathways within the cell. Thus, evidence mounts as to the importance of these pathways in PD including 1) how cells degrade certain proteins after their useful service life is over, 2) how mitochondria generate enough energy for the cell, and 3) how specific RNA molecules in the cell are managed.
One recent study showed that PINK1 (PARK6) and Parkin (PARK2) act together in one pathway affecting mitochondria inside the cell (1). An earlier study had shown that under energetically stressful conditions inside the cell that DJ1 (PARK7) and Parkin (PARK2) can interact with one another (2). These types of associations make it more likely that learning how to intervene in these specifically altered pathways may point the way to new treatments for this disorder.
Read detailed information on the genetic causes of Parkinson disease at the US National Library of Medicine’s Online Mendelian Inheritance in Man (OMIM) database (very detailed scientific information) as well as their Genetics Home Reference database (GHR) (geared to the layperson).
References:
1 - Lutz AK, Exner N, Fett ME, Schlehe JS, Kloos K, Lämmermann K, Brunner B, Kurz-Drexler A, Vogel F, Reichert AS, Bouman L, Vogt-Weisenhorn D, Wurst W, Tatzelt J, Haass C, Winklhofer KF. (2009) Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem.; 284(34):22938-51.
2 - Moore, D. J.; Zhang, L.; Troncoso, J.; Lee, M. K.; Hattori, N.; Mizuno, Y.; Dawson, T. M.; Dawson, V. L. (2005) Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Molec. Genet. 14: 71-84.
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