Ⅰ. INTRODUCTION 1 ⅠⅠ. MATERIALS AND METHODS 4 2-1. Fly stocks 4 2-2. Generation of transgenic fly lines 5 2-3. Microscope image acquisition 5 2-4. Immunostaining 6 2-5. Image processing and analyses 6 2-6. Rapid Iterative Negative Geotaxis (RING) assay 7 2-7. Separation of SDS–soluble and –insoluble fractions for Western blot analysis 7 2-8. Nuclear extraction 8 2-9. Western blot 8 2-10. Statistical analysis 9 2-11. Analysis of survival rate 9 2-12. Identification of Q-rich proteins 9 2-13. Calculation of co-localization score (CLS) 10 2-14. Calculation of cytoplasm to nucleus score (CNS) 10 2-15. Partial least square-discriminatory analysis (PLS-DA) 11 2-16. Functional enrichment analysis 12 2-17. Reconstruction of network model 13 ⅠⅠⅠ. RESULTS 14 3-1. Conversion of cytoplasmic mHtt to cleaved nuclear mHtt is critical for mHtt toxicity 14 3-2. Knockdown of strong mHtt interactors reduces cytoplasmic mHtt aggregates 25 3-3. Cytoplasmic localization and Q-richness are important for strong interaction with cytoplasmic mHtt proteins 46 3-4. In silico model predicts cytoskeletal regulators as strong interactors to modulate the amounts of cytoplasmic mHtt aggregates 56 3-5. Knockdown of strong mHtt interactors increases mHtt toxicity in neurons 62 ⅠV. DISCUSSION 74 V. REFERENCES 78 VI. SUMMARY IN KOREAN 88