Park8

PARK8 is an autosomal dominant PD caused by mutations of LRRK2 /dardarin. Clinical features were first described in large Japanese kindred (Nukada et al., 1978). They reported 36 patients in 5 generations. The age of onset ranged from 38 to 68 (mean = 53). Later the mean age of onset was reported as 51 ± 6 as the number of affected members increased (Funayama et al., 2002). Initial symptom was either gait disturbance or rest tremor. All of them showed L-dopa-responsive parkinsonism. Motor fluctuations and psychiatric side effects from L-dopa treatment can be seen. Clinical features are essentially similar to those of late onset sporadic PD except for slightly younger age of onset. Post-mortem examination in four patients from the original family showed pure nigral degeneration without Lewy body formation (Funayama et al., 2002). But later on another patient who came to autopsy from the same family showed nigral degeneration with Lewy bodies (Personal communication with Dr. K. Hasegawa).

The Western Nebraska family (Family D) reported by Wszolek et al. (1995), which inluded 18 patients in 5 generations, turned out to be PARK8. The age of onset was 48 to 78 (mean 63). Neuropathological features of this family are very interesting in that among the four patients who came to autopsy, one patient showed brain stem type Lewy body pathology; the second patient showed diffuse Lewy body disease pathology; the third patient showed nigral neuronal loss and gliosis with neurofibrillary tangles in the remaining nigral neurons without Lewy body formation; the fourth patient showed marked neuronal loss and gliosis in the nigra and locus coer-uleus without any inclusions or tau-positive accumulations (Wszolek et al., 2004). Four different pathological findings in the same family would indicate the difficulty of defining a disease entity by neuronal inclusions. Family A reported by Denson and Wszolek (1995) was also turned out to be PARK8.

PARK8 has been mapped to the centromeric region of chromosome 12 (Funayama

199 Ex 51

199 Ex 51

Fig. 7. Schematic presentation of LRRK2 and its mutations summarized from the literature, i.e., Zimprich et al. (2004), Paisan-Ruiz et al. (2004), and Kachergus et al. (2005). LRRK2 protein belongs to ROCO protein family, which is characterized by the presence of ROC domain and COR domain. Many of the ROCO proteins also have LRR, MAPKKK, and WD domains. See the text for the explanations of these domains. To date 6 missense mutations have been reported in the homology region. Exon 41 appears to be a mutational hot spot

Fig. 7. Schematic presentation of LRRK2 and its mutations summarized from the literature, i.e., Zimprich et al. (2004), Paisan-Ruiz et al. (2004), and Kachergus et al. (2005). LRRK2 protein belongs to ROCO protein family, which is characterized by the presence of ROC domain and COR domain. Many of the ROCO proteins also have LRR, MAPKKK, and WD domains. See the text for the explanations of these domains. To date 6 missense mutations have been reported in the homology region. Exon 41 appears to be a mutational hot spot et al., 2002). The causative gene was identified as LRRK2/dardarin (Zimprich et al., 2004; Paisan-Ruiz et al., 2004). LRRK2 stands for leucine-rich repeat kinase 2 and dardar means tremor in the Bask language where families of PARK8 are found. LRRK2 is a huge gene encompassing 144 kb and the open reading frame consists of 1449 base pairs in 51 exons. LRRK2 protein consists of 2527 amino acids and it is ubiquitously expressed in the cytoplasm of many organs. To date 6 missense mutations have been reported (Zimpricht et al., 2004; Paisan-Ruiz et al., 2004; Nichols et al., 2005) (Fig. 7).

LRRK2 protein belongs to the ROCO protein family. ROCO proteins are a group of proteins which has ROC and COR domain (Bosgraaf and Haastert, 2003). ROC stands for Ras in complex proteins belonging to the Ras/GTPase superfamily, and COR stands for carboxy terminal of ROC. In addition, many ROCO proteins have a LRR (leucine-rich repeat) domain, which has 3 to 16 leucine-rich repeats, a MAPKKK (mitogen-induced protein kinase kinase kinase) domain, and a WD domain, which is rich in tryptophan and aspartate repeats. The function of LRRK2 is still unknown but as it has protein kinase domain, it is likely that its role is phosphorylation of proteins that are important for the survival of nigral neurons. It is interesting to note that alpha-synuclein aggregates in PD are highly phosphorylated in Ser-129 (Fujiwara et al., 2002); therefore, it is an interesting question whether or not LRRK2 is in some way related to phosphorylation of alpha-synuclein.

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