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Nobutaka Hattori

Publications and source records attributed to Nobutaka Hattori.

At least 19 recordsLinked to original sources
PubMed2025

Genome-wide association study of copy number variations in Parkinson's disease.

OBJECTIVE: To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. METHODS: We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. RESULTS: The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. INTERPRETATION: The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Journal Article↗
PubMed2004

UCHL1 is a Parkinson's disease susceptibility gene.

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.

Adult↗
PubMed2004

Novel PINK1 mutations in early-onset parkinsonism.

PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance.

Adolescent↗
PubMed2004

Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients.

A point mutation of mitochondrial DNA at nucleotide position 3243 A to G is responsible for the genetic cause of diabetes. Otherwise, this mutation is also reported to occur as a somatic mutation, possibility because of oxidative stress. Because diabetes may cause oxidative stress, we hypothesized that accumulation of the somatic A3243G mutation in mitochondrial DNA may be accelerated by diabetes. DNA was extracted from blood samples of 290 nondiabetic healthy subjects (aged 0-60 years) and from 383 type 2 diabetic patients (aged 18-80 years). Then, the extent of somatic A3243G mutation in total mitochondrial DNA was detected by real-time polymerase chain reaction (PCR) using the TaqMan probe. The genotyping of ACE I/D or p22phox C242T was done by PCR or PCR-restriction fragment length polymorphism. Although the level of the A3243G mutation was negligible in the newborn group, it increased in healthy subjects aged 20-29 and 41-60 years. In diabetic patients, the mutational rate increased along with age and the duration of diabetes. In the middle-aged group (41-60 years old), the A3243G mutation accumulates fourfold higher in the diabetic patients than in the healthy subjects. Moreover, multiple regression analysis revealed that the most critical factor associated with this mutation in diabetic patients was the duration of diabetes. Furthermore, the genotype of DD, DI-CC (ACE-p22phox) has the highest mutational rate and the thickest intima-media thickness of the carotid artery. In conclusion, diabetes accelerates the accumulation of the somatic A3243G mutation in mitochondrial DNA, and this somatic mutation may be a marker for the duration of diabetes and atherosclerosis.

Adolescent↗
PubMed2004

Mitochondrial genome variation in eastern Asia and the peopling of Japan.

To construct an East Asia mitochondrial DNA (mtDNA) phylogeny, we sequenced the complete mitochondrial genomes of 672 Japanese individuals (http://www.giib.or.jp/mtsnp/index_e.html). This allowed us to perform a phylogenetic analysis with a pool of 942 Asiatic sequences. New clades and subclades emerged from the Japanese data. On the basis of this unequivocal phylogeny, we classified 4713 Asian partial mitochondrial sequences, with <10% ambiguity. Applying population and phylogeographic methods, we used these sequences to shed light on the controversial issue of the peopling of Japan. Population-based comparisons confirmed that present-day Japanese have their closest genetic affinity to northern Asian populations, especially to Koreans, which finding is congruent with the proposed Continental gene flow to Japan after the Yayoi period. This phylogeographic approach unraveled a high degree of differentiation in Paleolithic Japanese. Ancient southern and northern migrations were detected based on the existence of basic M and N lineages in Ryukyuans and Ainu. Direct connections with Tibet, parallel to those found for the Y-chromosome, were also apparent. Furthermore, the highest diversity found in Japan for some derived clades suggests that Japan could be included in an area of migratory expansion to Continental Asia. All the theories that have been proposed up to now to explain the peopling of Japan seem insufficient to accommodate fully this complex picture.

DNA, Mitochondrial↗
PubMed2004

Parkin attenuates manganese-induced dopaminergic cell death.

Manganese as environmental factor is considered to cause parkinsonism and induce endoplasmic reticulum stress-mediated dopaminergic cell death. We examined the effects of manganese on parkin, identified as the gene responsible for familial Parkinson's disease, and the role of parkin in manganese-induced neuronal cell death. Manganese dose-dependently induced cell death of dopaminergic SH-SY5Y and CATH.a cells and cholinergic Neuro-2a cells, and that the former two cell types were more sensitive to manganese toxicity than Neuro-2a cells. Moreover, manganese increased the expression of endoplasmic reticulum stress-associated genes, including parkin, in SH-SY5Y cells and CATH.a cells, but not in Neuro-2a cells. Treatment with manganese resulted in accumulation of parkin protein in SH-SY5Y cells and its redistribution to the perinuclear region, especially aggregated Golgi complex, while in Neuro-2a cells neither expression nor redistribution of parkin was noted. Manganese showed no changes in proteasome activities in either cell. Transient transfection of parkin gene inhibited manganese- or manganese plus dopamine-induced cell death of SH-SY5Y cells, but not of Neuro-2a cells. Our results suggest that the attenuating effects of parkin against manganese- or manganese plus dopamine-induced cell death are dopaminergic cell-specific compensatory reactions associated with its accumulation and redistribution to perinuclear regions but not with proteasome system.

Acetylcholine↗
PubMed2004

[Molecular biology for familial Parkinson's disease].

Parkinson's disease (PD) is the second most common neurodegenerative disorders. Recently, several forms of familial PD have been reported so far. Among them, several causative genes such as alpha-synuclein, UCH-L1, PINK1, and DJ-1 have been identified. Functional analysis on these causative genes may help us to explore the molecular mechanisms of nigral neuronal death in not only FPD but also sporadic form of PD. Thus, the identification of FPD gives us good information of etiologies of PD.

Humans↗
PubMed2003

Siah-1 facilitates ubiquitination and degradation of synphilin-1.

Parkinson's disease is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and appearance of Lewy bodies, cytoplasmic inclusions that are highly enriched with ubiquitin. Synphilin-1, alpha-synuclein, and Parkin represent the major components of Lewy bodies and are involved in the pathogenesis of Parkinson's disease. Synphilin-1 is an alpha-synuclein-binding protein that is ubiquitinated by Parkin. Recently, a mutation in the synphilin-1 gene has been reported in patients with sporadic Parkinson's disease. Although synphilin-1 localizes close to synaptic vesicles, its function remains unknown. To investigate the proteins that interact with synphilin-1, the present study performed a yeast two-hybrid screening and identified a novel interacting protein, Siah-1 ubiquitin ligase. Synphilin-1 and Siah-1 proteins were endogenously expressed in the central nervous system and were found to coimmunoprecipitate each other in rat brain homogenate. Confocal microscopic analysis revealed colocalization of both proteins in cells. Siah-1 was found to interact with the N terminus of synphilin-1 through its substrate-binding domain and to specifically ubiquitinate synphilin-1 via its RING finger domain. Siah-1 facilitated synphilin-1 degradation via the ubiquitin-proteasome pathway more efficiently than Parkin. Siah-1 was found to not facilitate ubiquitination and degradation of wild type or mutant alpha-synuclein. Synphilin-1 inhibited high K+-induced dopamine release from PC12 cells. Siah-1 was found to abrogate the inhibitory effects of synphilin-1 on dopamine release. Such findings suggest that Siah-1 might play a role in regulation of synphilin-1 function.

Animals↗
PubMed2003

Parkin cleaves intracellular alpha-synuclein inclusions via the activation of calpain.

Mutations in the alpha-synuclein and parkin genes cause heritable forms of Parkinson's disease. In the present study, we examined the possible functional relationship between the parkin and alpha-synuclein genes in a conditionally immortalized embryonic hippocampal cell (H19-7) line. Whereas transient transfection of alpha-synuclein into neuronal H19-7 cells caused the formation of its intracytoplasmic inclusions and a significant cell death, the combined overexpression of parkin restored the alpha-synuclein-induced decrease in cell viability to control levels. In addition, the overexpression of parkin was found to generate selective cleavage of alpha-synuclein. Furthermore, the cytoprotective effect of parkin on alpha-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor. Interestingly, the overexpression of parkin induced the activation of an intracellular cysteine protease, calpain, but not caspase, and the cytoprotective effect of parkin on alpha-synuclein cytotoxicity was significantly inhibited by the presence of calpain-specific inhibitors. In conclusion, our results suggest that parkin accelerates the degradation of alpha-synuclein via the activation of the nonproteasomal protease, calpain, leading to the prevention of alpha-synuclein-induced cell death in embryonic hippocampal progenitor cells.

Animals↗
PubMed2003

Pseudo-autosomal dominant inheritance of PARK2: two families with parkin gene mutations.

We report two families (Family S and Family N) with early-onset parkinsonism in two generations. The mode of inheritance appeared to be autosomal dominant, however, haplotye analysis suggested linkage to chromosome 6q25.2-27, the PARK2 locus, and all affected members were homozygotes in their haplotypes. In Family S, the affected father was married to unaffected mother, who carried one disease-linked haplotype at chromosome 6q25.2-27. In Family N, the unaffected mother carried one disease-linked haplotype. Quantitative PCR amplification analysis revealed exon 3 deletion in Family S and exon 5 deletion in Family N. The age of onset was from 18 to 22 years in Family S and 25 to 42 years in Family N. In both of their hometowns, most people lived in the same districts for many generations and consanguineous marriages had been common. Thus, the carrier state of the parkin gene might have been high in those communities, and marriage of a patient and a carrier is expected to result in autosomal dominant like inheritance. We conclude that PARK2 cannot be excluded even if the mode of inheritance appears as autosomal dominant, when the affected patients are young.

Aged↗
PubMed2003

Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration.

In the majority of patients with Parkinson's disease (PD), it is now clear that genetic factors contribute to the pathogenesis of PD, although the contribution of genetic and environmental factors remains to be elucidated. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of the high concordance in twins, increased risk among relatives of PD patients in case control and family studies, and the existence of familial PD based on single gene defects. Recently, several genes have been mapped and identified in patients with familial PD (FPD). alpha-Synuclein is involved in a rare dominant form of familial PD with dopa responsive parkinsonian features and Lewy body positive pathology. In contrast, parkin is responsible for autosomal recessive form of earlyonset PD with Lewy body-negative pathology. This form is identified with world-wide distribution among patients with young-onset PD. Furthermore, ubiquitin carboxy terminal hydrolase L1 (UCHL1) gene is responsible for an autosomal dominant form of typical PD, although only a single family has so far been identified with a mutation of this gene. In addition, DJ-1 has been identified as a causative gene for PARK7, a recessive form of familial PD. Now, a total of five causative genes including NR4A2 have been identified, and others such as PARK3, -4, -6, -8, -9, -10 have been mapped as hereditary forms of familial PD. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous disorder. However, the functions of causative genes may share a common pathway such as an ubiquitin-proteasome pathway. Thus, identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of not only familial PD, but also sporadic PD.

Humans↗
PubMed2003

Toward identification of susceptibility genes for sporadic Parkinson's disease.

To identify susceptibility genes for Parkinson's disease (PD) and to establish tailor-made medicine for PD, we studied 20 single nucleotide polymorphisms (SNPs) in 18 candidate genes for association with PD. We found that homozygosity for the V66M polymorphism of the BDNF gene occurs more frequently in PD patients than in unaffected controls and confirmed an association with the S18Y polymorphism of the UCHL1 gene. We further started microsatellite marker-based genome-wide association studies by using the pooled DNA method. We have finished checking approximately 6800 markers and found some significant associations (p=3.9 x 10(-6)) on chromosome 1 where other studies showed a linkage. Genes in linkage disequilibrium with these markers may be associated with pathogenesis of PD.

Adult↗
PubMed2003

Sensory neuropathy in autosomal recessive juvenile parkinsonism (PARK2).

Autosomal recessive juvenile parkinsonism (ARJP/PARK2) is a distinct clinical and genetic entity characterized by early-onset levodopa-responsive parkinsonism, foot dystonia, sleep benefit, and hyperactive tendon reflexes. We report a patient with genetically confirmed ARJP, who showed mild sensory disturbance and diminished deep tendon reflexes in the advanced stage. Nerve conduction studies revealed a sensory dominant neuropathy, which has not been described in ARJP. We suggest that peripheral neuropathy may occur in patients with advanced ARJP due to the loss of parkin protein function, although the function of parkin in the peripheral nervous system remains to be clarified.

Humans↗
PubMed2003

Autosomal recessive parkinsonism linked to parkin gene in a Tunisian family. Clinical, genetic and pathological study.

OBJECTIVES: To report clinical, pathological and genetic findings in a Tunisian kindred with autosomal recessive juvenile parkinsonism (AR-JP) linked to parkin gene. BACKGROUND: AR-JP has been mapped to chromosome 6q and is caused by several mutations of the parkin gene (Park 2). Pathological features in AR-JP are characterized by neuronal loss in substantia nigra (SN) without Lewy bodies (LB). PATIENTS AND METHODS: Three affected siblings with juvenile Parkinson's disease were studied. Pathological examination of the brain was performed in one of them. Linkage studies and mutation analysis of the parkin gene were performed. RESULTS: Clinical picture was characterized by the association of rest tremor, bradykinesia and rigidity. Parkinsonian signs markedly improved with levodopa treatment in the three siblings. Dystonia was observed in one patient and diurnal fluctuations of parkinsonian signs in another one. Linkage analysis showed homozygous haplotypes in patients as compared to unaffected individuals and mutation analysis of the parkin gene revealed a homozygous two-base AG deletion in exon 2 (101-102). Pathological examination of the brain in one patient showed marked loss of pigmented neurons with extraneuronal free melanin in the lateral and medial parts of the SN associated to a slight spongiosis and astrocytic gliosis. In the locus coeruleus, there was also loss of pigmented neurons without gliosis. No LB or neurofibrillary tangles were found neither by traditional nor by histo-immunological stainings. CONCLUSION: This Tunisian kindred with AR-JP linked to a micro-deletion of the parkin gene shows clinical similarities with the previously reported Japanese and European families. Pathological features of this kindred are compared to what has been reported in AR-JP families linked to large exonic deletions of this gene.

Adult↗
PubMed2003

Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain.

Parkin, a product of the causative gene of autosomal-recessive juvenile parkinsonism (AR-JP), is a RING-type E3 ubiquitin ligase and has an amino-terminal ubiquitin-like (Ubl) domain. Although a single mutation that causes an Arg to Pro substitution at position 42 of the Ubl domain (the Arg 42 mutation) has been identified in AR-JP patients, the function of this domain is not clear. In this study, we determined the three-dimensional structure of the Ubl domain of parkin by NMR, in particular by extensive use of backbone (15)N-(1)H residual dipolar-coupling data. Inspection of chemical-shift-perturbation data showed that the parkin Ubl domain binds the Rpn10 subunit of 26S proteasomes via the region of parkin that includes position 42. Our findings suggest that the Arg 42 mutation induces a conformational change in the Rpn10-binding site of Ubl, resulting in impaired proteasomal binding of parkin, which could be the cause of AR-JP.

Amino Acid Sequence↗
PubMed2003

Genotype-phenotype correlation: familial Parkinson disease.

Kindreds with Mendelian inheritance of Parkinson disease (PD) have been known since a long time ago. Nine loci have been mapped in familial PD by linkage study and four causative genes have been cloned. This paper discusses Park 1 and Park 2, the identification of which has brought about many advances in the studies on pathomechanism of PD. Investigations of these genes in familial PD have expanded their clinical and pathological phenotypes. However, to clarify the effect of mutations on these phenotypes, additional post-mortem neuropathological studies are required.

Brain↗
PubMed2003

Haploinsufficiency at the alpha-synuclein gene underlies phenotypic severity in familial Parkinson's disease.

To date, two point mutations, G209A and G88C, have been reported in the coding region of the alpha-synuclein gene in autosomal dominant familial Parkinson's disease. When translated, these lead to the missense mutations Ala53Thr and Ala30Pro, respectively. Reduced mRNA expression of the G209A allele was reported recently in a Greek-American family. Here, we show that alpha-synuclein mRNA is normally expressed in blood cells and report the results of an analysis of alpha-synuclein mRNA and protein expression in lymphoblastoid cell lines established from kindreds with the G209A and G88C mutations. mRNA expression was characterized using a TaqMan real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. We assessed five affected and three unaffected members of a German family with the G88C mutation and two affected members in different, unrelated Greek families with the G209A mutation. The ratio of wild-type to mutant alpha-synuclein allele expression ranged from 2.2 to 9.2 in the affected individuals with a severe clinical phenotype. The ratios of the expression levels of the wild-type to mutant alleles were only slightly decreased in mild cases and were less than 1.0 in two asymptomatic heterozygotes. Sequence analysis of the RT-PCR products showed only the presence of G in position 88 and G in position 209 in severely affected heterozygotes of the German and Greek families, respectively. High performance liquid chromatography/mass spectrometry demonstrated that, relative to wild-type alpha-synuclein, there is a reduction of Ala30Pro alpha-synuclein in lymphoblastoid cell lines originating from severely affected, but not mildly affected G88C/+ heterozygotes. Taken together, these data indicate that there is haploinsufficiency at the alpha-synuclein gene and that the ratio of expression of the wild-type to mutant alleles correlates with the severity of the clinical phenotype. Furthermore, these findings suggest that haploinsufficiency of alpha-synuclein mutations may contribute to disease progression in these forms of familial Parkinson's disease.

Age of Onset↗