Introduction
The following description is a series of important events that led to the identification and subsequent cloning of the PARK2 gene responsible for Parkinson’s disease.
Parkinson’s disease (PD) is a severe neurodegenerative disorder that impairs various important functions. The main problems include bradykinesia, rigidity, tremor, and postural instability and people affected by this disorder may fall in the age range of 65-80 (Daniel Weintraub et al., 2008). The etiology of this disease is believed to have a strong relationship with hereditary factors. As such, understanding the genetic predisposition of certain families to Parkinson’s disease became more vital. Gene mapping studies have made a significant contribution in assigning the location of specific genes to particular chromosome loci.
Main body
Quinn, Critchley, and Marsden (1987) conducted a study on two groups of patients with PD and reported that the patients in the age range of 21 and 40 years should be called “young onset Parkinson’s disease.” and those below 21 years should be identified as having “juvenile parkinsonism.” This was supported by another similar study that described the development of juvenile parkinsonism in four of the five siblings in a family (Takahashi et al., 1994).
One of the clinical forms of PD is autosomal recessive juvenile parkinsonism (AR-JP) which was regarded as a ‘familial’ type of PD and subsequent cloning of the gene responsible for the autosomal recessive type of ‘familial PD’ has contributed to the better understanding of sporadic cases of PD (Mizuno, Hattori, & Matsumine, 1998).
Hiroto Matsumine et al. (1997) conducted a linkage analysis study on AR-JP. According to this study, the AR-JP gene was found to be localized at chromosome 6q25.2-27 and co-segregated with another gene known as SOD2 (Mn-superoxide dismutase gene) between D6S437 andD6S264 markers. This study has chosen the SOD2 gene because its increased activity was reported to interfere with the pathology of PD.
Previously, it was believed that the alteration of mitochondrial DNA (mt DNA) function would result in neuronal death in PD (Di Monte DA, 1991). Mizuno et al (1995) described a reduction in the complex I of mitochondrial electron transfer complex and loss of the alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra of patients with PD. These defects could have led to the generation of neuronal toxins in patients with PD (Mizuno et al. 1998).
This process might have also led to impairment of the mitochondrial respiratory chain that facilitated the excess of superoxide anions release and subsequent enhancement of the SOD 2 gene activity (Hiroto Matsumine et al. 1997). Hence, the polymorphism of the SOD 2 gene has led to the finding of the AR-JP gene and drawn further research attention.
Further, linkage analysis studies were performed using the markers, D6S437, D6S1581, D6S1579, D6S305, D6S411, SOD2, D6S253, D6S1599, D6S1719, and D6S264 have revealed that the candidate gene for AR-JP was located near the 4-cM region between D6S437 andD6S264 (Saito et al.1998).
AR-JP was found to contribute to nigral neuron death. This was shown by a genetic model study that emphasized the relationship between the absence of Lewy body formation and neuron death in AR-JP (Matsumine, 1998). This study also described that AR-JP gene mapping to chromosome 6q25.2-27 was considered as an indication of functional single-gene mutations in the episode of nigral neural death.
These findings have finally led to a new candidate gene to be associated with the AR-JP.
Kitada et al. (1998) conducted genetic studies and described that AR –JP is caused by a mutation in a newly identified gene known as Parkin. This report described that this gene has 12 exons with 5 of them deleted in patients and shortening of a gene transcript in the brains of individuals with exon -4 deletions.
This report was further strengthened by another description that highlighted homozygous deletions in the parkin gene in individuals with AR-JP (Hattori et al.1998). Matsumine et al. (1998) conducted deletion studies while mapping the AR-JP gene and reported that exon search would help in promoting the cloning procedure of the AR-JP gene. As exon deletions were reported in an earlier study, understanding the key deletion mechanisms would help in a better understanding of molecular aspects of AR-JP. It was confirmed by subsequent immunohistochemical and immunoblotting studies that revealed the absence of parkin protein in the brains of AR-JP patients (Hattori & Mizuno, 1999). It may be inferred that the presence or absence of protein-induced immunological activity may play role in the pathogenesis of AR-JP.
Therefore it can also be concluded that that the onset of AR-JP occurs due to deletion mutation of the Parkin gene, PARK 2.Hence, mutation studies have not only allowed the proper association between the PARK2 gene and AR-JP but also strengthened the involvement of markers and SOD 2 gene.
From the available literature, it was understood that the age and onset of symptoms of AR-JP differ from PD and AR-JP was prevalent in Japanese families. The incidence of AR-JP in homozygous recessive individuals would clearly indicate that the disease runs in closely related families and seems much confined. As there are poor reports on the prevalence of AR-JP, further data is largely needed. Djarmati et al. (2004) described that parkin mutations are dependant on the ethnic origin of the patients.
Emerging trends in modern biology have facilitated the cloning of many candidate genes. Previous experiments have shed light on the function of parkin protein by studying the expression of mouse cDNA clones that are homologous to the human parkin gene (Kitada et al.2000).
On the whole, Parkinson’s disease is a severe neurological disorder with many etiological factors. Compelling evidence has revealed two forms of PD where juvenile parkinsonism has gained much research significance as it occurs at an early age of below 21. Considerable interest was also centered on ‘young onset Parkinson’ disease that occurs between 21 and 40 years of age.
One of the diagnostic features of AR-JP is neuronal injury and the absence of Lewy bodies.
In contrast, Lewy body formation is present in the native form of PD.
Genetic studies have identified autosomal recessive juvenile Parkinsonism (AR-JP) as a separate class of PD and the candidate gene was mapped to chromosome 6 between the D6S437 and D6S264 markers near SOD 2 loci by linkage analysis.
Mitochondrial function was also given much emphasis as its genome is reported to be involved in neuronal death. The involvement of altered SOD -2 gene function arising from the increasing superoxide anions of the mitochondrial respiratory chain has further strengthened the association of mitochondria with the etiology of PD. Other mitochondrial defects are also reported to contribute to neuronal toxicity.
Conclusion
Next, functional genomics has further elaborated the research and refined the existing knowledge of PD. As such gene deletion studies have clearly elucidated the importance of exon deletions in the brain of patients with AR-JP and connected this deletion mutation with the newly identified Parkin gene, PARK 2.
Further, it appears that there is much requirement to dissect the relationship between the pathogenesis of AR-JP and ethnicity due to its much confined familial form.
Park 2 gene has contributed enormously to the understanding of the polymorphic deletions that are considered pathogenic. It played a vital role in understanding nigral degeneration and facilitated further cloning experiments to get deep insights into the molecular biology of AR-JP.
References
Daniel Weintraub, Cynthia, Comella, & Stacy Horn.(2008). Parkinson’s Disease—Part 1: Pathophysiology, Symptoms, Burden, Diagnosis, and Assessment. Am J Manag Care, 14, S40-S48.
Quinn, N., Critchley, P., & Marsden, C.,D. (1987). Young onset Parkinson’s disease. Mov Disord,2,73-91.
Takahashi, H., Ohama, E., Suzuki, S., Horikawa, Y., Ishikawa, A., Morita, T., Tsuji, S., Ikuta F(1994).Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology, 44(3 Pt 1),437-41.
Hiroto Matsumine, Masaaki Saito, Satoe Shimoda-Matsubayashi, Hajime Tanaka,
Atsushi Ishikawa, Yuko Nakagawa-Hattori, Masayuki Yokochi, Tomonori Kobayashi,
Shuichi Igarashi, Hiroki Takano, Kazuhiro Sanpei, Ryoko Koike,Hideo Mori,
Tomoyoshi Kondo, Yoshihiko Mizutani, Alejandro, A., Schaffer, Yasuhiro Yamamura,
Shigenobu Nakamura, Shigeki Kuzuhara, Shoji Tsuji, Yoshikuni Mizuno (1997) “Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27.” Am. J. Hum. Genet, 60, 588-96.
Di Monte, D., A. (1991). Mitochondrial DNA and Parkinson’s disease. Neurology, 41(5 Suppl 2):38-42; discussion 42-3.
Mizuno, Y., Ikebe, S., Hattori, N., Nakagawa-Hattori, Y., Mochizuki, H., Tanaka, M., Ozawa, T.(1995). Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta, 1271, 265-74.
Saito, M., Matsumine, H., Tanaka, H., Ishikawa, A., Shimoda-Matsubayashi, S., Schäffer, A.A., Mizuno, Y., Tsuji, S.(1998).Refinement of the gene locus for autosomal recessive juvenile parkinsonism (AR-JP) on chromosome 6q25. 2-27 and identification of markers exhibiting linkage disequilibrium. J Hum Genet, 43, 22-31.
Matsumine, H. (1998). A loss-of-function mechanism of nigral neuron death without Lewy body formation: autosomal recessive juvenile parkinsonism (AR-JP).J Neurol, 245, (11 Suppl 3):P10-4.
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., Shimizu, N.(1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392, 605-8.
Mizuno. Y., Hattori, N., Matsumine, H. (1998). Neurochemical and neurogenetic correlates of Parkinson’s disease. Neurochem, 71, 893-902.
11. Hattori, N., Kitada, T., Matsumine, H., Asakawa, S., Yamamura, Y, Yoshino, H., Kobayashi, T.,Yokochi, M., Wang, M., Yoritaka, A., Kondo, T,, Kuzuhara, S, Nakamura, S, Shimizu, N., Mizuno, Y.(1998). Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol, 44, 935-41.
Hattori, N., & Mizuno, Y. (1999). Parkin gene and its function; a key to understand nigral degeneration. Rinsho Shinkeigaku 39, 1259-61.
Djarmati, A., Hedrich, K., Svetel, M., Schäfer, N., Juric, V., Vukosavic, S., Hering, R., Riess, O., Romac, S., Klein, C., Kostic, V.(2004). Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: Parkin mutation frequency depends on ethnic origin of patients. Hum Mutat, 23:525.
Kitada, T., Asakawa, S., Minoshima, S., Mizuno, Y., Shimizu, N.(2000). Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene. Mamm Genome, 11, 417-21.
Matsumine, H., Yamamura, Y., Hattori ,N., Kobayashi, T., Kitada, T., Yoritaka, A., Mizuno, Y. (1998). A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2). Genomics, 49, 143-6.