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Characterization of c9FTD/ALS pathogenesis using Drosophila as a model system

Characterization of c9FTD/ALS pathogenesis using Drosophila as a model system
Translated Title
초파리를 사용한 c9FTD/ALS의 병리 기전 연구
Kweon, Jung Hyun
DGIST Authors
Kweon, Jung Hyun; Lee, Sung BaeLee, Yun Il
Lee, Sung Bae
Lee, Yun Il
Issue Date
Degree Date
2017. 2
Access Rights
The original item will not be provided upon request from the author
C9ORF72FTDALSDendrite pathologySecretory pathway전두촉두 치매(FTD)루게릭병(ALS)수상돌기
Background The intronic GGGGCC (G4C2) hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a recently identified mutation, which causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Even though G4C2 repeat expansion is located at noncoding region, G4C2 hexanucleotide repeat can be translated into five types of dipeptide repeats (DPR) through repeat-associated non-ATG (RAN) translation. DPRs are found in brain tissues of c9FTD/ALS patients and there are a number of evidences about neuronal damage by DPRs. Here, I in-vestigated dendritic pathogenesis and dysfunctions of organelles in DPR-expressing Drosophila Class IV dendritic arborization (C4da) neurons. Results Toxic DPR-expressing neurons showed reduced number of dendrite branches and decreased intensity of membrane targeted fluorescence proteins. Dendritic secretory pathway organelles such as dendritic Endoplasmic Reticulum (ER) and Golgi outposts(GOPs) that are responsible for processing membrane targeted proteins at dendrites were impaired in DPR-expressing C4da neurons. Moreover, we observed reduced transcription level of CrebA, which is a master regulator of a ER-Golgi secretory pathway. Overexpression of CrebA in C4da neuron rescued intensity of membrane targeted fluores-cence protein, while it couldn’t restore the number of dendrite branches. Conclusion Our finding suggests the involvement of secretory pathway dysregulation in dendritic pathogenesis of c9FTD/ALS and possible restoration of a certain feature of dendrite defects through CrebA overexpression. ⓒ 2017 DGIST
Table Of Contents
I. INTRODUCTION -- 1.1 C9ORF72 mutation in FTD/ALS 1 -- 1.2 Dysfunction of intracellular organelles in c9FTD/ALS 2 -- II. METHODS -- 2.1 Fly stocks 5 -- 2.2 Immunohistochemistry 5 -- 2.2 Confocal microscopy imaging 6 -- 2.2 Image Processing 6 -- 2.2 RT-PCR 6 -- III. RESULTS -- 3.1 Dendrite defects in Drosophila Class IV da neurons expressing G4C2 and DPRs 8 -- 3.2 Secretory pathway disturbance by polyPR36 toxicity 9 -- 3.3 Nuclear localization of polyPR36 protein and decreased CrebA transcript 10 -- 3.4 Partial rescue by CrebA overexpression in polyPR36-expressing da neuron 11 -- IV. DISCUSSION 12 -- V. FIGURES 14
Brain and Cognitive Sciences
Related Researcher
  • Author Lee, Sung Bae SB LAB(Lab of Neurodegenerative diseases and Aging)
  • Research Interests Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
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