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Yazawa I.,Research Institute for Longevity science
Recent Patents on Regenerative Medicine | Year: 2012

Multiple system atrophy (MSA) is a neurodegenerative disease in which oligodendrocytes and neurons in the central nervous system (CNS) are affected. MSA is characterized by abnormal α-synuclein inclusions in oligodendrocytes, which are diagnostic of MSA. Formation of α-synuclein inclusions may be the primary lesions that eventually compromise neuronal function and viability. But little is known about the cellular mechanisms by which oligodendrocytic α- synuclein inclusions cause neuronal degeneration in MSA. Transgenic mice in which human wild-type α-synuclein was overexpressed in oligodendrocytes were generated as animal models of MSA. Oligodendrocytic inclusions induced neuronal accumulation of α-synuclein and progressive neuronal degeneration in the mouse CNS. In mouse neurons, endogenous α-synuclein binds to β-III tubulin in microtubules to form insoluble protein complexes, leading to neuronal dysfunction. The findings with mouse models suggest three pathological processes to underlie neurodegeneration in MSA: increase in neuronal expression of α-synuclein by oligodendrocytic inclusions, induction of neuronal accumulation of insoluble protein complexes by binding of α-synuclein to β-III tubulin and disturbance of α-synuclein modulation by neuronal activity. A positive perspective on the therapeutic target for MSA has been recently proposed. The methods to inhibit α-synuclein accumulation and those disclosed in related recent patent applications are summarized in this review. © 2012 Bentham Science Publishers. Source

Kinoshita M.,Shinshu University | Kondo Y.,Shinshu University | Yoshida K.,Shinshu University | Fukushima K.,Shinshu University | And 8 more authors.
Internal Medicine | Year: 2014

Objective Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is an adult-onset white matter disease that presents clinically with cognitive, mental and motor dysfunction. Several autopsy reports have indicated that the corpus callosum (CC), the largest bundle of white matter, is severely affected in patients with HDLS. The aim of this study was to evaluate corpus callosum atrophy (CCA) quantitatively in HDLS patients. Methods We assessed CCA in six genetically-proven HDLS patients (HDLS group), in comparison with that observed in 20 patients with vascular dementia (VaD group) and 24 age-matched patients without organic central nervous system (CNS) disease (non-CNS group). Using midsagittal MR images, five measurements of the CC were obtained: the width of the rostrum (aa'), body (bb') and splenium (cc'), the anterior to posterior length (ab) and the maximum height (cd). Next, the corpus callosum index (CCI) was calculated as (aa' + bb' + cc')/ab. Results All HDLS patients had white matter lesions in the CC and frontoparietal lobes on the initial MRI scans. Compared with that observed in the VaD and age-matched non-CNS groups, the CCI was significantly decreased in the HDLS group (with VaD group, p<0.01; with non-CNS group, p<0.01). Conclusion This study showed significant atrophy of the CC in all HDLS patients on the initial MRI scans obtained 6-36 months after onset. We propose that the early appearance of CCA, frequently accompanied by high-intensity in the genu and/or splenium, on T2 images is an important diagnostic clue to HDLS. © 2014 The Japanese Society of Internal Medicine. Source

Nakayama K.,Research Institute for Longevity science | Suzuki Y.,Research Institute for Longevity science | Yazawa I.,Research Institute for Longevity science
Biochemical and Biophysical Research Communications | Year: 2012

Multiple system atrophy (MSA) is a neurodegenerative disease caused by α-synuclein (α-syn) accumulation in oligodendrocytes and neurons. We generated a transgenic (Tg) mouse model in which human α-syn was overexpressed in oligodendrocytes. Our previous studies have revealed that oligodendrocytic α-syn inclusions induced neuronal α-syn accumulation, thereby resulting in progressive neuronal degeneration in mice. We also demonstrated that an insoluble complex of α-syn and β-III tubulin in microtubules progressively accumulated in neurons, thereby leading to neuronal degeneration. In the present study, we demonstrated that neuronal accumulation of the insoluble complex was derived from binding of α-syn to β-III tubulin and not from α-syn self-aggregation. Thus, interaction between α-syn and β-III tubulin plays an important role in neuronal α-syn accumulation in an MSA mouse model. © 2011 Elsevier Inc. Source

Suzuki Y.,Research Institute for Longevity science | Yazawa I.,Research Institute for Longevity science
International Journal of Clinical and Experimental Pathology | Year: 2011

Dentatorubral-pallidoluysian atrophy (DRPLA) is caused by the expansion of polyglutamine (polyQ) in atrophin-1 (ATN1), also known as DRPLA protein. ATN1 is ubiquitously expressed in the central nervous system (CNS), although selective regions of CNS are degenerated in DRPLA, and this selective neuronal damage gives rise to the specific clinical features of DRPLA. Accumulation of mutant ATN1 that carries an expanded polyQ tract seems to be the primary cause of DRPLA neurodegeneration, but it is still unclear how the accumulation of ATN1 leads to neurodegeneration. Recently, cleaved fragments of ATN1 were shown to accumulate in the disease models and the brain tissues of patients with DRPLA. Furthermore, proteolytic processing of ATN1 may regulate the intracellular localization of ATN1 and its fragments. Therefore, proteolytic processing of ATN1 may provide clues to disease pathogenesis and hopefully aid in the determination of molecular targets for effective therapeutic approaches for DRPLA. Source

Suzuki Y.,Research Institute for Longevity science | Jin C.,Research Institute for Longevity science | Yazawa I.,Research Institute for Longevity science
American Journal of Pathology | Year: 2014

Multiple system atrophy is an intractable neurodegenerative disease caused by α-synuclein (α-syn) accumulation in oligodendrocytes and neurons. With the use of a transgenic mouse model overexpressing human α-syn in oligodendrocytes, we demonstrated that oligodendrocytic α-syn inclusions induce neuronal α-syn accumulation, resulting in progressive neuronal degeneration. The mechanism through which oligodendrocytic α-syn inclusions trigger neuronal α-syn accumulation leading to multiple system atrophy is unknown. In this study, we identified cystatin C, an oligodendrocyte-derived secretory protein that triggers α-syn up-regulation and insoluble α-syn accumulation, in neurons of the mouse central nervous system. Cystatin C was released by mouse oligodendrocytes overexpressing human α-syn, and extracellular cystatin C increased the expression of the endogenous α-syn gene in wild-type mouse neurons. These neurons then accumulate insoluble α-syn and may undergo apoptosis. Cystatin C is a potential pathogenic signal triggering neurodegeneration in multiple system atrophy. Copyright © 2014 American Society for Investigative Pathology. Source

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