TOP ＞ Symposium

Symposium 17 Collaboration between neurochemistry (bench) and neurology (bedside) シンポジウム17 神経化学からみた神経疾患 -ベンチとベットサイドの間- SY17-1 Endosomal traffic jam as a unifying concept in Parkinson's disease パーキンソン病の共通病態としてのエンドソーム輸送障害 Hasegawa Takafumi（長谷川 隆文） Dept. of Neurol. Tohoku Univ. Grad. Sch. of Med. Although more than 90% of Parkinson's disease (PD) cases are sporadic, the identification of several genes linked to the familial forms of PD has offered great insight into the molecular basis of the disease. Of note, recent advance in molecular genetics have underscored the relevance of endosomal trafficking machinery in the pathogenesis of PD. For example, the discovery of pathogenic mutations in the genes of VPS35 (PARK17), a vital element of retromer complex, has implicated endosomal dysfunction in PD. The retromer complex mediates the retrograde transport of cargo from endosome to TGN. The retromer malfunction increases the lysosomal turnover of the mannose 6-phosphate receptor, thereby affecting the trafficking of cathepsin D, a lysosomal protease involved in the degradation of α-synuclein (αSYN), a culprit protein in PD. In addition, several genes (DNAJC13, DNAJC6, and GAK) encoding endocytic molecules in DNAJ/Hsp40 co-chaperone family have been identified as the PD-related genes. DNAJC13 is a responsible gene for the PARK21 familial PD. DNAJC13 is an endosome-resident protein originally identified as the mammalian homolog of receptor mediated endocytosis 8 (RME-8) in C. elegans. We recently found that pathogenic mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments showed that mutant DNAJC13 not only increased insoluble αSYN in fly head but also induced dopaminergic neurodegeneration and locomotor impairment. In this talk, I will review our current knowledge of the functional roles of endosomal trafficking in PD and will discuss how the failures in this machinery could facilitate the pathological alterations in this disease. SY17-2 A potential of blood exosomes as biomarkers for neurodegenerative diseases 神経変性疾患バイオマーカーとしての血液中エクソソームの可能性 Nagai Yoshitaka（永井 義隆） Dept. of Neurotherapeutics, Osaka Univ.Grad. Sch. Med. Recent advances toward developing disease-modifying therapies for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine diseases has successfully yielded many potential therapeutic candidates. However, most clinical trials have failed to prove the therapeutic efficacy of these candidates in human patients so far. One of the major causes of this large gap, so-called Valley of Death, is the limitation in evaluation methods of therapeutic efficacy of disease-modifying therapies in clinical trials. Since neurological phenotypes progress gradually in neurodegenerative disease patients, sensitive biomarkers that reflect pathological states are eagerly anticipated for rapid evaluation of the therapeutic efficacy. Biological fluids such as blood, urine, and cerebrospinal fluid (CSF) have great advantages in their accessibility as sources of biomarkers. Exosomes are extracellular vesicles (50-150nm in diameter) that are generated from multivesicular body, and are extracellularly secreted into the blood, urine, and CSF. They deliver various biomolecules such as RNAs and proteins, and function in intercellular communication. Recent studies report that neurodegenerative disease-associated proteins such as amyloid-β, tau, α-synuclein, and TDP-43 are found in exosomes, highlighting their potential roles in the pathogenesis and as diagnostic biomarkers. We recently found a novel role of exosomes in the intercellular delivery of molecular chaperones, to exert non-cell autonomous therapeutic effects on polyglutamine disease models, suggesting their protective roles. In this presentation, I will introduce our efforts in exploring potential biomarkers in blood exosomes, and discuss their potential as biomarkers for neurodegenerative diseases. SY17-3 Metabolomic analysis for biomarker discovery of Parkinson's disease メタボロミクスによるパーキンソン病のバイオマーカー探索 Hatano Taku（波田野 琢），斉木 臣二，服部 信孝 Department of Neurology, Juntendo University School of Medicine Parkinson’s disease (PD) is one of the most common neurodegenerative disorder caused by the loss of dopaminergic neuronal cells and presented with movement dysfunction. Although dopaminergic therapy partially ameliorates motor dysfunction, patients have many troublesome non-motor features, such as depression, dementia, sleep disorders and autonomic dysfunction. Therefore, disease modifying therapy should be needed. Thus, elucidating robust biomarkers associated with tracking disease progression and/or pathomechanisms of PD are essential. The pathogenesis of PD involves complex interactions between environmental and genetic factors. The pathological hallmarks of PD are the marked loss of dopaminergic neurons in the substantia nigra pars compacta, causing the depletion of dopamine in the striatum, as well as the presence of intracytoplasmic inclusions known as Lewy bodies. Neuronal loss and the formation of Lewy bodies have been detected not only in the SNc, but also in the locus coeruleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, para- and sympathetic postganglionic neurons, Meynert nucleus, amygdaloid nucleus and cerebral cortex. Thus, PD is recognized as a multicentric disorder and the pathomechanisms of PD might be associated with alteration of general metabolic pathway. Recently, we performed serum/plasma metabolomics analyses, which revealed the specific metabolic alteration of PD. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, anti-oxidant, and long-chain fatty acid. Whereas they had significantly higher levels of levodopa metabolites, and reactive oxidative stress than those of normal controls. Thus, metabolomics might be useful for discovery of candidate biomarker of PD. SY17-4 Endosome-associated molecules in Alzheimer's disease エンドソーム機能とアルツハイマー病 Takahashi Tetsuya（高橋 哲也） Dept of Clinical Neuroscience and Therapeutics, Hiroshima Univ. Alzheimer’s disease (AD) is the most common neurodegenerative disorder presenting dementia and up to half of the demented patients are diagnosed with AD in Japan. In AD, the deposition of amyloid plaque and presence of neurofibrillary tangles are cardinal features required for the pathologic diagnosis. Biochemical studies have revealed that amyloid plaque is composed of a 42-amino acid form of amyloid peptide (Aβ42) and hyperphosphorylated tau protein is the main constituent of neurofibrillary tangles, however, the precise relationship between amyloid plaque and neurofibrillary tangle is remained to be clarified. Besides these major pathological findings, characteristic vacuolar change so-called "granulovacuolar degeneration (GVD)" can be frequently seen in the pyramidal neurons in hippocampi of patients with AD. Although the origin of GVD bodies is not evident so far, we and other group reported that a molecule involved in the ESCRT (endosomal sorting complex required for transport) pathway could be a molecular marker of GVD indicative of endosomal origin of the GVD bodies. We also found that another endosome related protein APPL1 (Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is localised explicitly to "perisomatic granule"; a newly identified pathological finding specific to AD. In harmony with these findings, it has been shown that impairments in the endosome-lysosome pathway are related to the pathological findings of AD. The latest findings on the pathogenesis of AD will be discussed in terms of the endosome-lysosome pathway. SY17-5 Neuromuscular degeneration in spinal and bulbar muscular atrophy 球脊髄性筋萎縮症における神経筋システム変性 Katsuno Masahisa（勝野 雅央） Dept. of Neurology, Nagoya University Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, is an adult-onset, slowly progressive neurodegenerative disease caused by the expansion of a CAG repeat, encoding a polyglutamine tract, within the first exon of the androgen receptor (AR) gene. Increasing lines of evidence suggest that both motor neurons and skeletal muscle are primarily affected in SBMA.We showed that the expression levels of peroxisome proliferator-activated receptor-gamma (PPARg) were decreased in both neuronal and muscular cells bearing the pathogenic AR, and that treatment with pioglitazone, an activator of PPARg, improved the viability of these cellular models of SBMA. The oral administration of pioglitazone also suppressed NFκB signal activation both in the spinal cords and skeletal muscles of the SBMA mice. These findings suggest that PG suppresses neuromuscular degeneration of SBMA.We also tried to understand the pathophysiology of SBMA via identification of biomarkers that reflect biological changes during the preclinical progression of SBMA. As our results showed that serum creatinine starts to decrease approximately 15 years before the onset, we examined the creatine-creatinine metabolism in skeletal muscle. Intramuscular creatine concentrations were lower in with the autopsied specimen of SBMA subjects than in those with ALS subjects or controls. The protein and mRNA expression levels of muscle SLC6A8 were suppressed in subjects with SBMA. These results suggest that low serum creatinine concentration in subjects with SBMA is caused by impaired muscle uptake of creatine in addition to being caused by neurogenic atrophy.