Hideki Kimura

The Role of G-Protein-Coupled Receptor Kinase 5 in Pathogenesis of Sporadic Parkinson's Disease

Sporadic Parkinsons disease (sPD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the pathogenesis of the disease remains undetermined, phosphorylation of α-synuclein and its oligomer formation seem to play a key role. However, the protein kinase(s) involved in the phosphorylation in the pathogenesis of sPD has not been identified. Here, we found that G-protein-coupled receptor kinase 5 (GRK5) accumulated in Lewy bodies and colocalized with α-synuclein in the pathological structures of the brains of sPD patients. In cotransfected cells, GRK5 phosphorylated Ser-129 of α-synuclein at the plasma membrane and induced translocation of phosphorylated α-synuclein to the perikaryal area. GRK5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of α-synuclein. Genetic association study revealed haplotypic association of the GRK5 gene with susceptibility to sPD. The haplotype contained two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bound to YY1 (Yin Yang-1) and CREB-1 (cAMP response element-binding protein 1), respectively, and increased transcriptional activity of the reporter gene. The results suggest that phosphorylation of α-synuclein by GRK5 plays a crucial role in the pathogenesis of sPD.

Neuroprotective effect of oxidized galectin-1 in a transgenic mouse model of amyotrophic lateral sclerosis.

Abnormal accumulation of neurofilaments in motor neurons is a characteristic pathological finding in amyotrophic lateral sclerosis (ALS). Recently, we revealed that galectin-1, whose oxidized form has axonal regeneration-enhancing activity, accumulates in the neurofilamentous lesions in ALS. To investigate whether oxidized galectin-1 has a beneficial effect on ALS, oxidized recombinant human galectin-1 (rhGAL-1/ox) or physiological saline was injected into the left gastrocnemius muscle of the transgenic mice over-expressing a mutant copper/zinc superoxide dismutase (SOD1) with a substitution of histidine to arginine at position 46 (H46R SOD1). The H46R SOD1 transgenic mice, which represented a new animal model of familial ALS, were subsequently assessed for their disease onset, life span, duration of illness, and motor function. Furthermore, the number of remaining large anterior horn cells of spinal cords was also compared between the two groups. The results showed that administration of rhGAL-1/ox to the mice delayed the onset of their disease and prolonged the life of the mice and the duration of their illness. Motor function, as evaluated by a Rotarod performance, was improved in rhGAL-1/ox-treated mice. Significantly more anterior horn neurons of the lumbar and cervical cords were preserved in the mice injected with rhGAL-1/ox than in those injected with physiological saline. The study suggests that rhGAL-1/ox administration could be a new therapeutic strategy for ALS.

Female Preponderance of Parkinson’s Disease in Japan

A male preponderance of Parkinson’s disease (PD) has been reported in European countries and the USA. To verify this issue in Japanese patients with PD, we examined the age- and gender-specific prevalence of PD in Yamagata Prefecture (population 1,244,040), Japan. The prevalence of PD was 61.3/100,000 men and 91.0/100,000 women, showing that women were significantly more affected by PD than men (p < 0.001). Contrary to the findings in Europe and the USA, the results indicate a female preponderance of PD among the Japanese population.

A comprehensive study of repetitive transcranial magnetic stimulation in Parkinson's disease.

The clinical benefits of repetitive transcranial magnetic stimulation (rTMS) for Parkinsons disease (PD) remain controversial. We performed a comprehensive study to examine whether rTMS is a safe and effective treatment for PD. Twelve PD patients received rTMS once a week. The crossover study design consisted of 4-week sham rTMS followed by 4-week real rTMS. The Unified Parkinsons Disease Rating Scale (UPDRS), Modified Hoehn and Yahr Stage, Schwab and England ADL Scale, Actigraph, Mini-Mental State Examination, Hamilton Depression Scale, Wechsler Adult Intelligence Scale-revised, and cerebral blood flow (CBF) and cerebrospinal fluid (CSF) examinations were used to evaluate the rTMS effects. Under both drug-on and drug-off conditions, the real rTMS improved the UPDRS scores significantly, while the sham rTMS did not. There were no significant changes in the results of the neuropsychological tests, CBF and CSF. rTMS seems to be a safe and effective therapeutic option for PD patients, especially in a wearing-off state.

A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam

The deposition of tau inclusions is one of the neuropathological hallmarks in neurodegenerative disorders with dementia. We have reported that the N-terminal fragment of a human granin-like neuroendocrine peptide precursor (N-proSAAS) is accumulated in Pick bodies. However, it is unknown whether N-proSAAS is widely accumulated in tau inclusions in other tauopathies. Here, we performed an immunohistochemical examination using antibodies against both the N- and C-terminal sequence of proSAAS in the brains of patients with Alzheimers disease and parkinsonism-dementia complex on Guam. The antibody against N-proSAAS immunostained neurofibrillary tangles and neuritic plaques in both diseases, whereas the antibody against the C-terminal sequence of proSAAS did not. The results of the present study suggest that N-proSAAS or proSAAS-like molecules were trapped within the tau fibrils and accumulated in tau inclusions.

An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease.

The deposition of aggregated tau in cytoplasmic inclusions is one of the common neuropathological features in various dementing neurodegenerative disorders. At present, it remains unclear whether tau inclusions exert neurotoxicity or they are simply the consequence of neurodegeneration. In our approach for the analysis of the composition of tau inclusions, we detected the intense binding of anti-diacylglycerol kinase-zeta (DGK-zeta) antibodies to Pick bodies (PBs), which represent tau inclusions in Picks disease. The polyclonal antibodies were found to cross-react with a 21-kDa protein, but not with tau or ubiquitin, on Western blots of normal human brain extracts. Analysis of the 21-kDa protein by two-dimensional-gel electrophoresis and mass-spectrometry revealed that the protein is an N-terminal fragment of proSAAS (a human granin-like neuroendocrine peptide precursor). Our results suggest that sequestration of the N-terminal fragment of proSAAS in intracellular PBs may cause a functional disturbance of neurons in Picks disease.

Reply to the Letter by Lange et al.: Is Endotoxin an Environmental Cause of Parkinson's Disease?

We would like to thank Dr. J.H. Lange and colleagues for their valuable comments on our study on possible risk factors for Parkinson’s disease (PD). In our paper, contrary to the findings in Europe and the USA, we observed a higher prevalence of PD in women than men in Yamagata, an agricultural prefecture of Japan [1]. This female preponderance of PD was observed in people living in cities, where agricultural workers (farmers) are rare. For example, the ratio of men to women having PD is 1:1.7 in Yamagata City (population: 255,369), the seat of the prefectural government where farmers are rare. In the cities of Izumo (population: 80,639) [2] and Yonago (population: 132,315) [3], the female preponderance of PD is similar to that observed in Yamagata City. Therefore, it seems that a female preponderance of PD exists in both city dwellers and the rural Japanese population. Japan has become highly industrialized and the number of agricultural workers has dramatically declined in the past 50 years. The consumption of well water was common 50 years ago but is now rare. Nevertheless, the prevalence of PD has markedly increased during this period of time. For example, in Kyoto, the ageand sex-adjusted prevalence of PD was 34.4/100,000 in 1978 and increased to 112.7/ 100,000 in 2001 [4]. This increase may be the result of a better prognosis, resulting in an increased prevalence of PD in the Japanese population. The above changes of the industrial structure, the social environment and the PD prevalence in Japan do not support the hypotheses that belonging to the rural population, exposure to pesticides and/or herbicides, and consumption of well water are risk factors for PD in Japan. However, as Lange and colleagues point out, it is necessary to conduct extensive ecological investigations of PD which include data on smoking rates, tea/coffee/alcohol consumption, exposure to environmental agents (e.g. pesticides and endotoxins), as well as other factors. We are currently initiating such a study in the Yamagaya population registry.