Long Sun Ro

Genetic testing in spinocerebellar ataxia in Taiwan: Expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease

DNA tests in normal subjects and patients with ataxia and Parkinsons disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA‐binding protein gene and suggests that SCA8 may also be a cause of typical PD.

Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.

Recent results show that brain glucocorticoids are involved in the dysregulation of fear memory extinction in post-traumatic stress disorder patients. The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction. To achieve these goals, male SD rats, fear-potentiated startle paradigm, and Western blot were used. We found that (1) systemic administration of the synthetic glucocorticoid agonist dexamethasone (DEX) facilitated extinction of conditioned fear in a dose-dependent manner (0.05, 0.1, 0.5, or 1.0 mg/kg, i.p.); (2) systemic administration of the glutamate NMDA receptor antagonist (±)-HA966 (6.0 mg/kg, i.p.) and intra-amygdala infusion of the NMDA receptor antagonists MK801 (0.5 ng/side, bilaterally) or D,L-2-amino-5-phosphonovaleric acid (AP5, 2.0 ng/side, bilaterally) blocked the DEX facilitation effect; (3) the corticosteroid synthesis inhibitor metyrapone (25 mg/kg. s.c.) blocked extinction and this was prevented by co-administration of NMDA receptor agonist D-cycloserine (DCS, 5.0 mg/kg, i.p.); (4) co-administration of DEX and DCS in subthreshold doses provided a synergistic facilitation effect on extinction (0.2 and 5 mg/kg, respectively). Control experiments indicated that co-administration of DEX and DCS did not alter the expression of conditioned fear and the effect was not due to lasting damage to the amygdala. These results suggest that glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction.

Neuroprotective effects of granulocyte‐colony stimulating factor in a novel transgenic mouse model of SCA17

J. Neurochem. (2011) 118, 288–303.

Epidemiological and genetic studies of myotonic dystrophy type 1 in Taiwan

To investigate the prevalence and genetic characteristics of myotonic dystrophy type 1 (DM1) in Taiwan, DM-suspected patients and their families identified during the period of 1990–2001 had their clinical records reevaluated and the CTG repeat sizes at the DM1 locus examined. A total of 96 subjects belonging to 26 families were identified as DM1 patients, which gave a minimal disease prevalence of 0.46/100,000 inhabitants. Clinical anticipation was frequently observed in affected families, even in some parent-child pairs with transmission contraction of the CTG repeat size. The inverse correlation between age at onset and CTG repeat length was significant only in patients with small expansions. In addition, a DM1 carrier with a childhood-onset son was found to have CTG length heterogeneity in the range of 40–50, indicating that premutation alleles could be unstable during gametogenesis as well as in somatic tissues. Our data demonstrated that DM1 is a rare disease in Taiwan and showed that transmission contraction of repeat size is more likely to occur in alleles with large repeats.

Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury.

Recent studies have shown that opioid treatment can reduce pro-inflammatory cytokine production and counteract various neuropathic pain syndromes. Granulocyte colony-stimulating factor (G-CSF) can promote immune cell differentiation by increasing leukocytes (mainly opioid-containing polymorphonuclear (PMN) cells), suggesting a potential beneficial role in treating chronic pain. This study shows the effectiveness of exogenous G-CSF treatment (200 µg/kg) for alleviating thermal hyperalgesia and mechanical allodynia in rats with chronic constriction injury (CCI), during post-operative days 1–25, compared to that of vehicle treatment. G-CSF also increases the recruitment of opioid-containing PMN cells into the injured nerve. After CCI, single administration of G-CSF on days 0, 1, and 2, but not on day 3, relieved thermal hyperalgesia, which indicated that its effect on neuropathic pain had a therapeutic window of 0–48 h after nerve injury. CCI led to an increase in the levels of interleukin-6 (IL-6) mRNA and tumor necrosis factor-α (TNF-α) protein in the dorsal root ganglia (DRG). These high levels of IL-6 mRNA and TNF-α were suppressed by a single administration of G-CSF 48–144 h and 72–144 h after CCI, respectively. Furthermore, G-CSF administered 72–144 h after CCI suppressed the CCI-induced upregulation of microglial activation in the ipsilateral spinal dorsal horn, which is essential for sensing neuropathic pain. Moreover, the opioid receptor antagonist naloxone methiodide (NLXM) reversed G-CSF-induced antinociception 3 days after CCI, suggesting that G-CSF alleviates hyperalgesia via opioid/opioid receptor interactions. These results suggest that an early single systemic injection of G-CSF alleviates neuropathic pain via activation of PMN cell-derived endogenous opioid secretion to activate opioid receptors in the injured nerve, downregulate IL-6 and TNF-α inflammatory cytokines, and attenuate microglial activation in the spinal dorsal horn. This indicates that G-CSF treatment can suppress early inflammation and prevent the subsequent development of neuropathic pain.

Balò's concentric sclerosis: MRI

We report a case of Balòs concentric sclerosis. In the past, the diagnosis was usually made post mortem. In this case, we found that CT demonstrated only low-density lesions, but not their concentric pattern. However, MRI showed a striking feature, reminiscent of histopathology of Balòs concentric sclerosis, and played an important role in antemortem diagnosis of this rare demyelinating disease.

Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1β release through the inhibition of Nogo-A expression

BackgroundNogo-A is a member of the reticulon family of membrane-associated proteins and plays an important role in axonal remodeling. The present study aimed to investigate alterations in Nogo-A expression following traumatic brain injury (TBI)-induced inflammation and neuronal damage.MethodsA weight-drop device was used to deliver a standard traumatic impact to rats. Western blot, RT-PCR and ELISA were used to analyze the expression of Nogo-A and IL-1β. Nogo-A antisense, and an irrelevant control oligonucleotide was intracerebroventricularly infused. We also performed H & E staining and luxol fast blue staining to evaluate the neuronal damage and demyelination resulting from TBI and various treatments.ResultsBased on RT-PCR and western blot analyses, the expression of Nogo-A was found to be significantly upregulated in the hippocampus beginning eight hours after TBI. In addition, TBI caused an apparent elevation in IL-1β levels and severe neuronal damage and demyelination in the tested animals. All of the TBI-associated molecular and cellular consequences could be effectively reversed by treating the animals with the anti-inflammatory drug indomethacin. More importantly, the TBI-associated stimulation in the levels of both Nogo-A and IL-1β could be effectively inhibited by a specific Nogo-A antisense oligonucleotide.ConclusionsOur findings suggest that the suppression of Nogo-A expression appears to be an early response conferred by indomethacin, which then leads to decreases in the levels of IL-1β and TBI-induced neuron damage.

Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese

BACKGROUND Impaired ubiquitin-proteasome system function may contribute to the pathogenesis of Parkinsons disease (PD). METHODS We conducted a case-control study in a cohort of 517 PD cases and 518 ethnically matched controls to investigate the association of ubiquitin specific proteases USP24 rs487230 C>T, USP40 rs1048603 C>T, and ubiquitin thiolesterase UCHL1 rs5030732 A>C polymorphisms with the risk of PD. RESULTS No significant difference in the genotype or allele distribution was found between PD and controls. After stratification by age, the genotype and allele frequencies of USP24 rs487230 are significantly different between PD and controls >or=60 years of age (P=0.035 and 0.013, respectively). Multivariable logistic regression with adjusting for onset age and sex showed that, in a dominant model, USP24 T-carrying genotype was associated with risk reduction in developing PD in individuals >or=60 years of age (OR=0.61; 95% CI=0.41-0.90, P=0.010). This is also true for T allele (OR=0.64; 95% CI=0.44-0.91, P=0.023). When examining the interaction between genes on PD risk without age stratification, the protective effect of USP24 CT/TT genotype on PD risks was strengthened by the USP40 T-carrying genotype (OR=0.42; 95% CI=0.22-0.81, P=0.009) and UCHL1 C-carrying genotype (OR=0.67; 95% CI=0.47-0.97, P=0.032). CONCLUSIONS Our results suggest that USP24 alone plays a role in PD susceptibility among Taiwanese people >or=60 years of age, or acting synergistically with USP40 and UCHL1 in the total subjects.

Heterozygous mutations affecting the epimerase domain of the GNE gene causing distal myopathy with rimmed vacuoles in a Taiwanese family.

OBJECTIVES Studies of distal myopathy with rimmed vacuoles (DMRV) revealed that most patients had mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. However, the correlation between GNE mutations and clinical features was not fully understood. PURPOSES To report the correlation between the clinical features and genetic analysis of DMRV patients. PATIENTS AND METHODS The clinical presentations, histopathological findings, image studies, and genetic analyses of two patients with DMRV from a Taiwanese family were studied. RESULTS Two compound heterozygous mutations, Ile 241 Ser and Arg 246 Gln, located in the epimerase domain, were identified in both patients, who were of the same generation. In addition, the elder sister showed a progressive muscular dystrophy course with severe quadriceps and trunk muscle involvement. CONCLUSION The compound heterozygous mutations in the epimerase domain of the GNE gene are important in the severe phenotype of DMRV. However, the mechanisms leading to this phenotypic heterogeneity still remain to be elucidated.

Serial MRI studies in pathologically verified Balò's concentric sclerosis.

We report serial MRI studies in a patient with Balòs concentric sclerosis, who presented with a progressive weakness in the right limbs of 10 day duration. Serial MR images revealed several concentric lesions characterized by layer by layer of demyelinated and myelinated appearance and multiple plaques in the white matter. Pathological study of a biopsy of a concentric lesion (which was performed to rule out neoplasm) further confirmed this diagnosis. These MR findings resolved in correspondence with clinical improvement. The patient was almost completely normal 1 year later. In conclusion, in this case, we found that MRI could show the striking feature reminiscent of the histopathologic findings of Balòs concentric sclerosis and played an important role in antemortem diagnosis of this rare demyelinating disease.