Huntington's disease (HD) is an autosomal dominant inheritable neurodegenerative disorder currently without effective treatment. It is caused by an expanded polyglutamine (poly Q) tract in the ...corresponding protein, huntingtin (htt), and therefore suppressing the huntingtin expression in brain neurons is expected to delay the onset and mitigate the severity of the disease. Here, we have used small interfering RNAs (siRNAs) directed against the huntingtin gene to repress the transgenic mutant huntingtin expression in an HD mouse model, R6/2. Results showed that intraventricular injection of siRNAs at an early postnatal period inhibited transgenic huntingtin expression in brain neurons and induced a decrease in the numbers and sizes of intranuclear inclusions in striatal neurons. Treatments using this siRNA significantly prolonged model mice longevity, improved motor function and slowed down the loss of body weight. This work suggests that siRNA-based therapy is promising as a future treatment for HD.
Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 ...causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.
DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that ...mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt-expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington's disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology.
The ɛ
4 allele of
APOE is a well-characterized genetic risk factor for late-onset Alzheimer disease (LOAD). Nevertheless, using high-density single nucleotide polymorphisms (SNPs), there have only ...been a few studies involving genetic association and linkage disequilibrium (LD) analyses of in and around the
APOE. Here, we report fine mapping of a genomic region (about 200 kb) including the
APOE in Japanese using 260 SNPs (mean intermaker distance, 0.77 kb). A case-control study demonstrated that 36 of these SNPs exhibited significance after adjustment for multiple testing. These SNPs are located in a genomic region including four genes,
PVRL2,
TOMM40,
APOE and
APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean |
D′|
=
0.914). These data suggest that the three genes other than
APOE, i.e.
PVRL2,
TOMM40 and
APOC1, could also yield a predisposition to LOAD.
Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at ...E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5-E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.
We studied 20 single nucleotide polymorphisms in 18 candidate genes for association with Parkinson's disease. We found that homozygosity for the V66M polymorphism of the brain‐derived neurotrophic ...factor (BDNF) gene occurs more frequently in patients with Parkinson's disease than in unaffected controls (χ2 = 5.46) and confirmed an association with the S18Y polymorphism of the UCH‐L1 gene. Our results provide genetic evidence supporting a role for BDNF in the pathogenesis of Parkinson's disease.
Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinson's disease (PD). ZNS (300 mg/day) given to a patient with PD who incidentally had convulsive ...attacks, ameliorated the attacks and, surprisingly, his parkinsonian symptoms. We, therefore, carried out an open trial of ZNS on nine patients with PD. Patients were given 50–200 mg/day ZNS in addition to their anti-PD drugs. Seven clearly showed lessening of symptoms, especially wearing-off. We speculate that long lasting activation of dopamine synthesis by ZNS ameliorates parkinsonian symptoms, in particular wearing-off.
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