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Most of the patients with Parkinson’s disease (PD) are sporadic. However, Since identification of monogenic forms of PD, the contribution of genetic factors to the pathogenesis of sporadic PD is proposed as one of major risk factors. Indeed, this is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies. Thus, the functional analysis for the gene products for familial PD provides us a good hint to elucidate the pathogenesis of nigral degeneration. For example, although α-synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features, this molecule is a major component of and Lewy bodies (LBs). In contrast, Park2 (parkin-related disease) is the most frequent form among patients with young-onset PD. However, Park2 brains generally lack the formation of LBs. In the other word, parkin responsible for Park2 is essential for the formation of LBs. Thus, both α-synuclein and parkin are speculated to share a common pathway. Here, we reviewed the parkin function and molecular mechanisms of Park2.

Parkinson’s Disease (PD) is a common neurodegenerative disorder that is characterized by the progressive loss of dopamine (DA) neurons. Accompanying the loss the of DA neurons is the accumulation of Lewy bodies and neurites, intracytoplasmic proteinaceous inclusions that contain alphasynuclein, synphilin-1, components of the ubiquitin proteasomal pathway and parkin. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, DJ-1, PINK-1, LRRK2, and parkin. Understanding the molecular mechanisms by which mutations in familial-linked genes cause PD holds great promise for unraveling the mechanisms by which DA neurons degenerate in PD. Parkin is E3-ubiquitinprotein ligase that ubiquitinates itself and promotes its own degradation. Familial associated mutations of parkin have impaired ubiquitin ligase function suggesting that this may be the cause of familial autosomal recessive PD. Parkin might be required for formation of Lewy bodies as Lewy bodies are absent in patients with parkin mutations. Parkin interacts with and ubiquitinates the alphasynuclein interacting protein, synphilin-1. Formation of Lewy-body-like ubiquitinpositive cytosolic inclusions occurs upon coexpression of alpha-synuclein, synphilin-1 and parkin. Nitric oxide inhibits Parkin’s E-3 ligase activity and its protective function by nitric oxide through S -nitrosylation both in vitro and in vivo . Nitrosative and oxidative stress link parkin function with the more common sporadic form of Parkinson’s disease and the related α-synucleinopathy, DLBD. Development of new therapies for PD and other disorders associated with nitrosative and oxidative stress may follow the elucidation of the pathways by which NO S -nitrosylates and inhibits parkin. Moreover, parkin and alpha-synuclein are linked in common pathogenic mechanism through their interaction with synphilin-1 and parkin may be important for the formation of Lewy bodies.

Our genetic knowledge of Parkinson’s disease (PD) is moving forward at an impressive speed. In less then 10 years family-based linkage analysis and positional cloning have led to the identification of several genes for familial forms of PD, which has been of critical importance to the scientific advance of PD research as the causal genes have offered new tools to model and understand pathways leading to neurodegeneration in PD.

The etiology for Parkinson’s disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 ( LRRK2 ), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2 -associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2 -associated parkinsonism.

A locus for a dominant form of PD has been mapped to the pericentromeric region of chromosome 12 in a Japanese family. We have confirmed linkage in two families of European ancestry and identified mutations in the gene for LRRK2 in these two and four additional families with dominantly inherited PD. All mutations are located in highly conserved domains of the gene. The LRRK2 protein belongs to the ROCO protein family, and includes a ras domaine (ras of complex proteins) and a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of Families A and D, six post-mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson’s disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology and progressive supranuclear palsy-like pathology. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

We here summarize the results of genetic investigations on a series of 82 parkinsonian patients from 60 families in Taiwan. We found 13 parkin patients in 7 families (12%), 2 PINK1 sibs from 1 family, and 1 LRRK2 patient from 1 family with I2012T mutation. We also identified SCA2 in 8 patients from 5 families (8%) and SCA3 in 3 patients from 1 family, all presenting with parkinsonian phenotype. In the available patients with parkin, PINK1 , SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson’s disease. We concluded that the genetic causes contributed to about 25% of our series of familial parkinsonism. The parkin mutations and SCA2 were the most frequent genetic causes in our series with Chinese ethnicity. The results of DAT scan indicated that bilateral putamen was essentially involved in various genetically-caused familial parkinsonism.

Structural imaging studies often reveal relatively limited findings in Parkinsonian disorders, as the most profound changes are neurochemical and hence better revealed by functional studies such as PET or SPECT. However, newer magnetic resonance techniques such as spectroscopy, diffusion weighted imaging, diffusion tensor imaging and magnetization transfer have shown promise in differentiating between idiopathic Parkinson’s and the atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. We review here recent advances in functional imaging as well as in structural studies of basal ganglia disorders. Functional studies may give insights into mechanisms underlying disease pathogenesis, as well as neurochemical alterations.

In recent years transcranial sonography (TCS) has become a widely used method for the visualization of the brain parenchyma through the intact scull. Using TCS, our group discovered changes of the echotexture — namely increased echogenicity — at the substantia nigra (SN) in about 90% of patients with Parkinson’s disease (PD). These results assessed with an interrater reproducibility of r =0.8 in several studies have been confirmed by several other groups. In contrast increased SN echogenicity is rarely found in patients with atypical or symptomatic Parkinsonian syndromes, providing a valuable tool for differential diagnosis. Interestingly, increased SN echogenicity can also be found in about 8 to 10% of healthy subjects. In PET analyses more than 60% of these clinically healthy individuals show a subclinical reduction of the striatal ^18F-Dopa uptake indicating an alteration of the dopaminergic nigrostriatal system and nigral cell loss. Furthermore, it was possible to demonstrate that this ultrasound finding has a functional impact as subjects with an increased echogenicity of the SN (i) showed more frequently clinical symptoms of asymmetric hypokinesia with increasing age and (ii) developed more often and more severe Parkinsonian side effects when treated with neuroleptic therapy for neuropsychiatric disorders. Longitudinal studies indicate that the ultrasound signal does not change in the course of the disease. Moreover, presymptomatic carriers of mutations causative for monogenetic PD display the same echofeature as their relatives already affected by the disease. These findings indicate that increased SN echogenicity constitutes a biomarker for vulnerability of the nigrostriatal system in healthy subjects and eventually PD in a subgroup of persons with additional risk factors.

Ideally, animal models of Parkinson’s should reproduce the clinical manifestation of the disease, a loss of some but not all dopaminergic neurons, a loss of some non dopaminergic neurons and alphasynuclein positive inclusions resembling Lewy bodies. There are at least three ways to develop animal models of PD. The first two are based on the etiology of the disease and consist in 1) reproducing in animals the mutations seen in inherited forms of PD; 2) intoxicating animals with putative environmental toxins causing PD. The last method currently used, which is not exclusive of the first two, is to try to reproduce the molecular or biochemical changes seen post-mortem in the brain of patients with PD. In this review we discuss the advantages and the drawbacks in term of neuroprotection of the currently used models.

Cell cultures for Parkinson’s disease research have the advantage of virtually unlimited access, they allow rapid screening for disease pathogenesis and drug candidates, and they restrict the necessary number of animal experiments. Limitations of cell cultures, include that the survival of neurons is dependent upon the culture conditions; that the cells do not develop their natural neuronal networks. In most cases, neurons are deprived from the physiological afferent and efferent connections. In Parkinson’s disease research, mesencephalic slice cultures, primary immature dopaminergic neurons and immortalized cell lines — either in a proliferating state or in a differentiated state — are used. Neuronal cultures may be plated in the presence or absence of glial cells and serum. These different culture conditions as well as the selection of outcome parameters (morphological evaluation, viability assays, biochemical assays, metabolic assays) have a strong influence on the results of the experiments and the conclusions drawn from them. A primary example is the question of whether L-Dopa is toxic to dopaminergic neurons or whether it provides neurotrophic effects: In pure, neuronal-like cultures, L-Dopa provides toxicity, whereas in the presence of glial cells, it provides trophic effects when applied. The multitude of factors that influence the data generated from cell culture experiments indicates that in order to obtain clear-cut and unambiguous results, investigators need to choose their model carefully and are encouraged to verify their main results with different models.