TOP ＞ Symposia

Symposia Membrane trafficking and neurodegenerative diseases／メンブレントラフィッキングと神経変性疾患 3S5-1 Age-related endocytic dysfunction is involved in Alzheimer’s disease pathology. Nobuyuki Kimura Dept Alzheimer Dis Res, NCGG The membrane traffic in endocytic pathway, so-called endocytosis, is the fundamental process required for cellular physiology such as the regulation of cell surface receptor signaling. It is widely accepted that β-amyloid protein (Aβ) is the key factor for Alzheimer’s disease (AD) pathogenesis, and the cleavage of Aβ from its precursor protein, β-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. Evidently, the intracellular accumulation of abnormally enlarged endosomes is frequently observed in neurons of the brains with early stage of AD, indicating that endocytic dysfunction occurs in AD patient neurons. Strikingly, recent genome-wide association studies revealed that several endocytosis-related genes were associated with AD onset. Cytoplasmic dynein is a microtubule-based motor protein required for minus-end-directed axonal transport, including retrograde trafficking of endosomes. Dynactin, another microtubule-associated protein, binds to dynein intermediate chain (DIC) to form a functional complex that enables motor activity. We previously showed that aging attenuates the interaction between DIC and dynactin in nonhuman primate brain, and dynein dysfunction reproduced age-dependent endocytic pathology, resulting in the intracellular accumulation of APP and Aβ. We also confirmed that endocytic pathology is observed in glial cells, and endocytic dysfunction disrupts Aβ clearance in astrocytes. Moreover, endocytic dysfunction can disrupt neuronal physiological functions such as synaptic vesicle transport and neurotransmitter release. Thus the “traffic jam” in endocytic pathway may be involved in AD pathogenesis, and then it may represent a brand-new target for the development of new therapeutics. 3S5-2 Molecular mechanisms of Parkinson's disease: implication of membrane trafficking Takafumi Hasegawa Dept Neurol. Grad Sch Med, Tohoku Univ Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by progressive movement disability and a variety of non-motor symptoms. The neuropathology of PD consists of the loss of dopaminergic neurons in the midbrain and the appearance of neuronal inclusions called Lewy bodies, which contain insoluble alpha-synuclein (aSyn) protein. Recent advances in genetic and biochemical studies have provided unifying conceptual frameworks of the pathogenesis of PD. Particularly, membrane trafficking has aroused special attention as an initiator or enhancer of the neurodegenerative process that leads to PD. Defects in the cellular trafficking pathway result in synaptic dysfunction and the accumulation of misfolded aSyn. Likewise, changes in intracellular sorting and degradation profoundly influence the cellular trafficking of aggregated aSyn, thereby facilitating the cell-to-cell spreading of noxious aSyn species in a prion-like manner. Here, I will review our current knowledge of the functional roles of membrane trafficking in PD and will discuss how this cellular process could induce or facilitate the functional and pathological alterations in this disease. 3S5-3 Prion propagation through sortilin degradation Suehiro Sakaguchi，Keiji Uchiyama Div Mol Neurobiol. Ins Enz Res, Tokushima Univ The conformational conversion of the normal cellular prion protein, a membrane glycoprotein abundantly expressed by neurons, into the abnormally folded, amyloidogenic prion protein is an essential pathogenic event in prion disease. Sortilin is a membrane protein mediating intracellular trafficking of proteins. Sortilin interacted with the normal and abnormal prion proteins and transported them to lysosomes for degradation. Overexpression of sortilin reduced the abnormal prion protein in prion-infected cells. In contrast, downregulation of sortilin increased the abnormal prion protein in prion-infected cells. The normal prion protein was also increased by downregulation of sortilin in prion-uninfected cells. Interestingly, prion infection reduced sortilin by promoting lysosomal degradation of sortilin. We then intracerebrally inoculated prions into sortilin-knockout (KO) and control wild-type (WT) mice. Sortilin-KO mice developed prion disease and died significantly earlier than WT mice. Sortilin-KO mice also accumulated the abnormal prion protein from the earlier stages of infection, compared to control WT mice. These results indicate that prions could propagate themselves by inducing degradation of sortilin. 3S5-4 Elucidating pathogenesis of congenital myopathy caused by defective membrane remodeling and lipid homeostasis Tetsuya Takeda，Kenshiro Fujise，Kaho Seyama，Yasuka Yamashita，Hiroshi Yamada，Kohji Takei Grad Sch Med Dent Pharma Sci, Okayama Univ Congenital myopathies are muscle disorders characterized by muscle weakness and associated disabilities. Centronuclear myopathies (CNM) are a group of congenital myopathies that share common symptoms including severe hypotonia and hypoxia-requiring breathing. The CNM symptoms are strongly related to structural defects of T-tubule that is a plasma membrane invagination required for excitation-contraction (E-C) coupling of muscle cells. Previous studies demonstrated that CNM mutations were mapped in DNM2, BIN1 and MTM1 genes. DNM2 encodes a large GTPase dynamin2, while BIN1 encodes a BAR domain protein amphiphysin2, two proteins known to regulate membrane remodeling. Instead, MTM1 encodes myotubularin, a ubiquitously expressed phosphoinositide (PI) 3-phosphatase required for lipid homeostasis. These results suggest that T-tubule defects in CNM are developed by aberrant membrane remodeling and lipid homeostasis, but precise mechanisms of CNM pathogenesis remain unclear.In this study, we analyzed impact of CNM mutations on the function of dynamin2, amphiphysin2 and myotubularin using membrane tubulation assay in mouse myoblast cells. We found that CNM mutations affected multiple aspects of membrane remodeling such as membrane tubule formation and maintenance and membrane tubule dynamics. Possible models of CNM pathogenesis based on our updated data will be discussed at the meeting.