Symposium

Symposium 18 JSN Symposium Autophagy: molecules to medicine in the neurological disorders シンポジウム18 日本神経化学会理事会企画シンポジウムオートファジー　分子から神経疾患治療まで

SY18-1 Promotion of neuroaxonal degeneration mediated by autophagy オートファジーによる神経変性の促進 Araki Toshiyuki（荒木敏之），若月修二 Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry Research on the mechanism of injury-induced axonal degeneration (Wallerian degeneration) revealed that axonal degeneration is an active process involving transcriptional regulations and enzymatic reactions. Axonal degeneration is observed as part of the pathology in many neurological disorders, including neurodegenerative disorders, and causes key symptoms. Subcellular reactions regulating axonal degeneration are independent from those for apoptosis, in principle, and therefore, prevention of axonal degeneration may constitute an important therapeutic strategy against neurodegenerative disorders.We have recently shown that ZNRF1, a ubiquitin ligase, regulates stability of microtubules constituting cytoskeletal structure in axons via regulating degradation of AKT and thereby controlling its downstream phosphorylation reaction cascade. We also found that the phosphorylation cascade also promotes autophagy in degenerating axons.Autophagy in neuronal cells has been shown to degrade misfolded proteins and thereby maintain integrity of healthy neurons. In addition to this basal level autophagy, activated autophagy has been observed in degeneration axons, but its pathophysiological roles have been unclear. We have shown that autophagy in degenerating axons promotes axonal degeneration. We also found that autophagy-mediated production of ATP contributes to the exposure of phosphatidylserine (PS) ― an “eat-me” signal for phagocytes ― on degenerating axons, and is required for normal recruitment of phagocytes to axonal debris in vivo.		SY18-2 Pathophysiology and therapeutic development of autophagy disease SENDA/BPAN オートファジー病SENDA/BPANの病態と治療開発 Muramatsu Kazuhiro（村松一洋） Department of Pediatrics, Jichi Medical University, Tochigi, Japan Autophagy is an essential biological phenomenon for life support of every organism; that is, a protein degradation system indispensable for quality control and maintenance of cells. And also, it is featured by the Nobel Prize in 2016 and one of the important research fields in Japan leading the world. The influence on the physiological function caused by the failure of autophagy is a broad variety of such as tumor, infectious disease, cardiomyopathy, immune function, aging, diabetes, fatty liver, allergy, neurodegeneration and so on.There are diseases in which the failure of the autophagy directly causes. In recent years, two diseases SENDA (static encephalopathy of childhood with neurodegeneration in adulthood or BPAN) and Vici syndrome have already been found at the pediatric field. These diseases caused by autophagy dysfunctions are collectively referred to as "autophagy diseases".SENDA / BPAN, caused by the mutation in autophagy-related gene WDR45, is a neurodegenerative disease established as a direct pathogenesis of autophagy dysfunction. Although it is a rare genetic refractory disease, it has been found that the phenotype has a wide spectrum. There are examples in which it develops with refractory epilepsy, independently walking is possible even if it over 20 years old, and it is considered that there are still many undiagnosed patients. The pathophysiology is still unknown, for examples such as lesions mainly in the central nervous system, rapid progression over 20 years old and iron deposits in the brain. Since there is no fundamental treatment method, it is urgent task to elucidate the pathophysiology first. Based on this, we are investigating for new drug that inhibit the onset and progression, and developing into a breakthrough therapeutic method.

SY18-3 Development of anti-Parkinson's disease medicines focusing on autophagy/mitophagy modulation オートファジー、マイトファジーに着目したパーキンソン病治療法開発 Saiki Shinji（斉木臣二） Dept. of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan Autophagy is well-preserved from yeasts to human, finely tuned, a protein degradation system indispensable for cellular homeostasis. Also, molecular pathogenesis of various diseases such as cancers and neurodegenerative diseases has been revealed to be linked to insufficient or excessed autophagy. In this background, we have tried to identify autophagy regulation chemicals to give relief or complete remedy to devastating diseases, especially Parkinson’s disease (PD). Some PD-associated gene products like parkin and PINK1 coordinately control mitochondrial autophagy (PINK1/parkin-mediated mitophagy) under sensing system of mitochondrial membrane potentials. Recently, PINK1/parkin independent mitophagy has been established and those are increasing evidences that it would be druggable target. In this context, I would like to summarize our data focusing on modulation of autophagy/mitophagy by chemicals using various cellular PD models. Also, I would like to show our data associated with lysosomal trafficking and autophagic flux regulated by intrinsic factors.		SY18-4 Membrane dynamics and physiological roles of autophagy オートファジーの膜動態と生理的意義 Mizushima Noboru（水島昇） Dept. of Mol. Biol., Grad. Sch. of Med, Univ. of Tokyo Autophagy is a major degradation system in the cell. Intracellular components are sequestered by autophagosomes and then degraded upon fusion with lysosomes. Yeast genetic studies have identified more than 40 autophagy-related (ATG) genes. Many of these genes are conserved in higher eukaryotes, which brought about an exponential expansion of autophagy research in various organisms including mammals. Furthermore, accumulating evidence suggests the relationship between autophagy and human diseases. However, there are a lot of questions and new directions remaining in the autophagy field. In the symposium, after providing a general overview, recent progresses on the membrane dynamics and physiological functions of autophagy in mice and zebrafish will be discussed.