Biomedical subjects

Shin Kwak

Publications and source records attributed to Shin Kwak.

At least 19 recordsLinked to original sources

PubMed2006

Calcium-permeable AMPA channels in neurodegenerative disease and ischemia.

Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.

Amyotrophic Lateral Sclerosis↗

PubMed2006

A positron emission tomography study on the role of nigral lesions in parkinsonism in patients with amyotrophic lateral sclerosis.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) sometimes exhibit parkinsonism, but the lesion responsible for parkinsonism has not been extensively studied. OBJECTIVE: To test whether nigrostriatal system dysfunction is responsible for parkinsonism in ALS. DESIGN: From the 182 ALS patients who were admitted to our neurology ward during the past 10 years, we extracted all the patients who satisfied the criteria of both parkinsonism and ALS. SETTING: The University of Tokyo Hospital. METHODS: We conducted [(18)F]L-dopa and [(11)C]N-methylspiperone positron emission tomography and technetium Tc 99m hexamethylpropyleneamine oxime single-photon emission computed tomography studies on 5 patients with ALS manifesting overt parkinsonism. RESULTS: Two male and 3 female patients (average age, 63.2 +/- 5.8 years) had ALS for an average of 28.6 +/- 21.5 months and had parkinsonism for an average of 15.2 +/- 11.4 months. Features of their parkinsonism were characterized by outstanding bradykinesia without resting tremor or dementia. The results of positron emission tomography studies indicated normal nigrostriatal function, but those of single-photon emission computed tomography demonstrated decreased blood flow in the frontotemporal cortices. CONCLUSION: It is likely that parkinsonism in ALS is due to cortical lesions rather than nigrostriatal dysfunction and that both symptoms are the clinical manifestation of frontotemporal dementia with motor neuron diseases, including classic ALS.

Aged↗

PubMed2006

Aging of complex heart rate dynamics.

We reveal unexpected origins of age induced departure from 1/f-type temporal scaling in healthy human heart rate. Contrary to the widely established view, we provide evidence that age induced dynamical imbalance in the autonomic control is not due to the emergent functional dominance of the sympathetic nervous system (SNS), but due to emerging (age dependent) relative dynamic dominance of the parasympathetic nervous system function. In particular, we demonstrate that the age induced alterations of healthy heart rate dynamics asymptotically resemble those in so-called primary autonomic failure with neurogenic SNS dysfunction and in other neurodegenerative disorders, including Parkinson's disease even without known autonomic abnormalities. Based upon this, we propose a novel picture of "autonomic aging," characterized by an insufficiency of the SNS function to cope dynamically with various environmental stimuli.

Adaptation, Physiological↗

PubMed2006

Slow and selective death of spinal motor neurons in vivo by intrathecal infusion of kainic acid: implications for AMPA receptor-mediated excitotoxicity in ALS.

Excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been proposed to play a major role in the selective death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), and motor neurons are more vulnerable to AMPA receptor-mediated excitotoxicity than are other neuronal subclasses. On the basis of the above evidence, we aimed to develop a rat model of ALS by the long-term activation of AMPA receptors through continuous infusion of kainic acid (KA), an AMPA receptor agonist, into the spinal subarachnoid space. These rats displayed a progressive motor-selective behavioral deficit with delayed loss of spinal motor neurons, mimicking the clinicopathological characteristics of ALS. These changes were significantly ameliorated by co-infusion with 6-nitro-7-sulfamobenso(f)quinoxaline-2,3-dione (NBQX), but not with d(-)-2-amino-5-phosphonovaleric acid (APV), and were exacerbated by co-infusion with cyclothiazide, indicative of an AMPA receptor-mediated mechanism. Among the four AMPA receptor subunits, expression of GluR3 mRNA was selectively up-regulated in motor neurons but not in dorsal horn neurons of the KA-infused rats. The up-regulation of GluR3 mRNA in this model may cause a molecular change that induces the selective vulnerability of motor neurons to KA by increasing the proportion of GluR2-lacking (i.e. calcium-permeable) AMPA receptors. This rat model may be useful in investigating ALS etiology.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Novel splice variants of human ADAR2 mRNA: skipping of the exon encoding the dsRNA-binding domains, and multiple C-terminal splice sites.

We report here two previously unknown alternative splice sites in the mRNA of human adenosine deaminase acting on RNA type 2 (ADAR2), an RNA editing enzyme. One splices out the whole of exon 2, which encodes two double-stranded RNA-binding domains (dsRBDs), resulting in a frameshift that introduces a stop codon in the downstream exon. This variant accounts for between 13% and 20% of the total ADAR2 mRNA in each developmental stage and brain region examined, even though its translated product is not expressed at levels that are detectable by Western blot analysis. The other new splice site is located in exon 9, 83 nucleotides downstream of the stop codon for the long C-terminus, resulting in a new 3' untranslated region (UTR) that is about 80 bp longer than the previously reported short C-terminus. The variant produced by this splice site has a stop codon at the same site as that in ADAR2 mRNA containing canonical exons 9 and 10, and is predicted to be translated as an enzymatically active ADAR2 protein. With these two additional splice sites, a total of 48 mRNA variants are theoretically possible, because each splicing event occurs independently. Among them, variants containing the long C-terminus are translated in human brains in situ, implying that alternative splicing in the 3' UTR of ADAR2 might regulate translational efficiency and mRNA stability in vivo.

3' Untranslated Regions↗

PubMed2005

Underediting of GluR2 mRNA, a neuronal death inducing molecular change in sporadic ALS, does not occur in motor neurons in ALS1 or SBMA.

Deficient RNA editing of the AMPA receptor subunit GluR2 at the Q/R site is a primary cause of neuronal death and recently has been reported to be a tightly linked etiological cause of motor neuron death in sporadic amyotrophic lateral sclerosis (ALS). We quantified the RNA editing efficiency of the GluR2 Q/R site in single motor neurons of rats transgenic for mutant human Cu/Zn-superoxide dismutase (SOD1) as well as patients with spinal and bulbar muscular atrophy (SBMA), and found that GluR2 mRNA was completely edited in all the motor neurons examined. It seems likely that the death cascade is different among the dying motor neurons in sporadic ALS, familial ALS with mutant SOD1 and SBMA.

Aged↗

PubMed2005

Expression profile of AMPA receptor subunit mRNA in single adult rat brain and spinal cord neurons in situ.

The differential expression of AMPA receptor subunit mRNA was analyzed in the adult rat brain and spinal cord using quantitative RT-PCR with laser capture microdissection. The expression of all four AMPA receptor subunits was demonstrable, with the mRNA expression level for GluR2 being the highest in all the brain areas and neuronal subsets examined. Both the absolute expression level of GluR2 mRNA and its expression relative to the other subunits were the lowest in motoneurons. The unique AMPA receptor expression profile of motoneurons may render them selectively vulnerable to AMPA receptor-mediated excitotoxicity.

Animals↗

PubMed2005

Noisy vestibular stimulation improves autonomic and motor responsiveness in central neurodegenerative disorders.

The vestibular nerves are known to influence neuronal circuits in the medullary cardiovascular areas and, through the cerebellar vermis, the basal ganglia and the limbic system. By means of noisy galvanic vestibular stimulation (GVS), it might be possible to ameliorate blunted responsiveness of degenerated neuronal circuits of patients with multi system atrophy or Parkinson's disease, or both. We evaluated the effect of 24-hour noisy GVS on long-term heart rate dynamics in 7 patients with multi system atrophy and on daytime trunk activity dynamics in 12 patients with either levodopa-responsive Parkinson's disease or levodopa-unresponsive parkinsonism. Six of the latter patients were also examined for cognitive performance by means of a continuous performance test. Short-range or high-frequency fluctuations of heart rate were significantly increased by the noisy GVS compared with sham stimulation, suggestive of improved autonomic, especially parasympathetic, responsiveness. Long-range antipersistency of trunk activity patterns probed by an autocorrelation measure was significantly increased by the noisy GVS, suggestive of quickening of bradykinesic rest-to-active transitions. The mean reaction time of the continuous performance test was also significantly decreased by the noisy GVS, without significant changes in either the omission or commission error ratios, which is suggestive of improved motor execution during the cognitive task. In conclusion, the noisy GVS is effective in boosting the neurodegenerative brains of patients with multi system atrophy or Parkinson's disease, or both, including those unresponsive to standard levodopa therapy; it is also effective in improving these patients' autonomic and motor responsiveness.

Aged↗

PubMed2005

Excitotoxicity and ALS: what is unique about the AMPA receptors expressed on spinal motor neurons?

It has been repeatedly reported that spinal motor neurons are selectively vulnerable to AMPA receptor-mediated excitotoxicity. Therefore, identifying the uniqueness of AMPA receptors that are expressed on motor neurons, especially in individuals affected with sporadic amyotrophic lateral sclerosis (ALS) is essential for elucidating the etiology of this disorder. The mechanism that initiates motor neuronal death appears to be an exaggerated influx of Ca(2+) through AMPA receptors. The determinants that affect this Ca(2+) influx are Ca(2+) permeability, which is regulated by the presence of the GluR2 subunit and by RNA editing at the Q/R site of GluR2; channel desensitization, which is regulated by alternative splicing at the flip/flop site and by RNA editing at the R/G site of GluR subunits; and receptor density on the cell surface, which is controlled by many factors including regulatory proteins, direct phosphorylation and RNA editing at the Q/R site. This review focuses on recent progress on the molecular dynamics of AMPA receptors and discusses the pathophysiology of selective motor neuron death mediated by AMPA receptors in individuals affected with sporadic ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Quantitative evaluation of the pyramidal tract segmented by diffusion tensor tractography: feasibility study in patients with amyotrophic lateral sclerosis.

PURPOSE: Diffusion tensor imaging can evaluate the cerebral white matter quantitatively using fractional anisotropy (FA) and also can extract a certain tract by tractography, but these two have been used separately and not combined. The purpose of this study was to assess the clinical feasibility of ROI analysis using diffusion tensor tractography (DTT) in patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Sixteen patients with ALS (9 limb-onset type, 7 bulbar-onset type) and nine age-matched volunteers were studied. DTT of the corticobulbar tract (DTT-CBT) and corticospinal tract (DTT-CST) were visualized by free software (dTV/VOLUME-ONE). Regions-of-interest (ROIs) were semi-automatically placed on the tracts defined by DTT methods, and FA values within the ROIs were measured. RESULTS: Mean FA values of ALS patients in the ROIs along the DTT-CST (bulbar-onset: 0.574, limb-onset: 0.594) were significantly lower than those of controls (DTT-CST: 0.629) (p<0.05). The mean FA of DTT-CBT of the bulbar-onset type (0.509) was significantly lower than that of the limb-onset type (0.558) and that of volunteers (0.561). CONCLUSION: DTT could segmentate certain white matter tracts and evaluate them quantitatively. It could depict the subtle changes between subtypes of ALS as well as the changes between the patients and volunteers.

Amyotrophic Lateral Sclerosis↗

PubMed2005

[AMPA receptor-mediated neuronal death and amyotrophic lateral sclerosis].

Explore the source record for details and available documents.

Adenosine Deaminase↗

PubMed2004

Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis.

One plausible hypothesis for selective neuronal death in sporadic amyotropic lateral sclerosis (ALS) is excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, which are a subtype of ionotropic glutamate receptors. The Ca2+ conductance of AMPA receptors differs markedly depending on whether the GluR2 (or GluR-B) subunit is a component of the receptor. The properties of GluR2 are generated posttranscriptionally by RNA editing at the Q/R site in the putative second membrane domain (M2), during which the glutamine (Q) codon is substituted by an arginine (R) codon. AMPA receptors containing the unedited form of GluR2Q have high Ca2+ permeability in contrast to the low Ca2+ conductance of those containing the edited form of GluR2R. The role of Ca(2+)-permeable AMPA receptors, particularly GluR2 Q/R site RNA editing status, in neuronal death has been clearly demonstrated both in mice deficient in editing at the GluR2 Q/R site and in mice transgenic for an artificial Ca(2+)-permeable GluR2 subunit. We analyzed the expression level of mRNA of each AMPA receptor subunit in individual motor neurons, as well as the editing efficiency of GluR2 mRNA at the Q/R site in the single neuron level in control subjects and ALS cases. There was no significant difference as to the expression profile of AMPA receptor subunits or the proportion of GluR2 mRNA to total GluRs mRNA between normal subjects and ALS cases. By contrast, the editing efficiency varied greatly, from 0% to 100%, among the motor neurons of each individual with ALS, and was not complete in 44 of them (56%), whereas it remained 100% in normal controls. In addition, GluR2 editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS, spinocerebellar degeneration and normal control groups. Thus, GluR2 underediting occurs in a disease specific and region selective manner. GluR2 modification by RNA editing is a biologically crucial event for neuronal survival, and its deficiency is a direct cause of neuronal death. Therefore, marked reduction of RNA editing in ALS motor neurons may be a direct cause of the selective motor neuron death seen in ALS. It is likely that the molecular mechanism underlying the deficiency in RNA editing is a reduction in the activity of ADAR2, a double- strand RNA specific deaminase. The restoration of this enzyme activity in ALS motor neurons may open the novel strategy for specific ALS therapy.

Amyotrophic Lateral Sclerosis↗

PubMed2004

1/f scaling in heart rate requires antagonistic autonomic control.

We present systematic evidence for the origins of 1/f -type temporal scaling in human heart rate. The heart rate is regulated by the activity of two branches of the autonomic nervous system: the parasympathetic (PNS) and the sympathetic (SNS) nervous systems. We examine alterations in the scaling property when the balance between PNS and SNS activity is modified, and find that the relative PNS suppression by congestive heart failure results in a substantial increase in the Hurst exponent H towards random-walk scaling 1/ f(2) and a similar breakdown is observed with relative SNS suppression by primary autonomic failure. These results suggest that 1/f scaling in heart rate requires the intricate balance between the antagonistic activity of PNS and SNS.

Adaptation, Physiological↗

PubMed2004

GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in the adult human brain.

We report the cloning of human GluR4c, an alternative splicing isoform of GluR4. Similar to rodent and chick GluR4c mRNA, human GluR4c had a 113-bp insert containing a stop codon, resulting in a short C terminus. The expression of human GluR4c was widespread in the brain, and was upregulated with development in the cerebellum and cerebral cortex where the level of it was about 30% of total GluR4 mRNA in adult stage. The GluR4 subunit may play a pivotal role in regulating channel properties as well as trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the adult human brain.

Adult↗

PubMed2004

Glutamate receptors: RNA editing and death of motor neurons.

The aetiology of sporadic amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, is largely unknown. Here we show that there is a defect in the editing of the messenger RNA encoding the GluR2 subunit of glutamate AMPA receptors in the spinal motor neurons of individuals affected by ALS. This failure to swap an arginine for a glutamine residue at a crucial site in the subunit, which occurs normally in the affected brain areas of patients with other neurodegenerative diseases, will interfere with the correct functioning of the glutamate receptors and may be a contributory cause of neuronal death in ALS patients.

Amyotrophic Lateral Sclerosis↗

PubMed2004

Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down's syndrome brains.

In human brain, developmental up-regulation in RNA editing at the Q/R site was evident in GluR5 and GluR6, but GluR2 editing in the white matter was down-regulated. Each ADAR mRNA expression was up-regulated in the gray matter, whereas differently regulated in the white matter. ADAR2 mRNA was not overexpressed in the brains of Down's syndrome subjects, nor was there any evidence of changes in the RNA editing efficiency of their GluRs.

Adenosine Deaminase↗

PubMed2003

1/f noise outperforms white noise in sensitizing baroreflex function in the human brain.

We show that externally added 1/f noise more effectively sensitizes the baroreflex centers in the human brain than white noise. We examined the compensatory heart rate response to a weak periodic signal introduced via venous blood pressure receptors while adding 1/f or white noise with the same variance to the brain stem through bilateral cutaneous stimulation of the vestibular afferents. In both cases, this noisy galvanic vestibular stimulation optimized covariance between the weak input signals and the heart rate responses. However, the optimal level with 1/f noise was significantly lower than with white noise, suggesting a functional benefit of 1/f noise for neuronal information transfer in the brain.

Baroreflex↗

PubMed2003

Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain.

The ionotropic glutamate receptor (GluR) subunits GluR2, GluR5 and GluR6 are subject to RNA editing at their Q/R sites, resulting in significant alterations in the channel properties of the receptors. RNA editing at the Q/R site of GluRs is both developmentally and regionally regulated. Here we provide the first quantitative measurements of both mRNAs of the GluR subunits and mRNAs of the RNA editing enzymes ADAR1-ADAR3 in a comparison of the efficiency of editing at the Q/R site with the expression levels of ADAR mRNA in human brain. We demonstrate that the Q/R site of GluRs in white matter is edited significantly less than in grey matter. In addition, by means of quantitative reverse transcription-polymerase chain reaction methods, we demonstrate that the relative abundance of ADAR2 mRNA to GluR2 mRNA is significantly lower in white matter than in grey matter and that the GluR2 Q/R site editing decreased only when the ratio of ADAR2 mRNA (not that of ADAR1 mRNA) to GluR2 mRNA dropped below a threshold (20 x 10(-3)). These results suggest that Q/R site of GluRs editing is regulated in a regional, and hence presumably cell-specific, manner and that the GluR2 Q/R site editing is critically regulated by ADAR2 in human brain.

Adenosine Deaminase↗