Molecular network analysis of ALS/FTD-responsible gene C9orf72

2016 Fiscal Year Final Research Report

• Project/Area Number: 25430054
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Satoh Jun-ichi 明治薬科大学, 薬学部, 教授 (30274591)
• Co-Investigator(Renkei-kenkyūsha): ARIMA Kunimasa 国立病院機構小諸高原病院, 院長 (20250227)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: C9orf72 / ALS / FTD / 結合タンパク質 / 標的遺伝子 / 分子ネットワーク / Smcr8 / NNA1

Outline of Final Research Achievements

Expanded GGGGCC repeats located in the first intron of the C9orf72 (C9) gene represent the most common genetic abnormality of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, the molecular mechanism underlying neurodegeneration in C9ALS remains unknown. We studied molecular network of genes and proteins involved in C9ALS pathology from public datasets. We found that C9 repeat RNA-binding proteins play a key role in posttranscriptional RNA processing. Gene expression of extracellular matrix proteins (ECM) is reduced in C9ALS iPSC-derived motor neurons. Genes involved in the regulation of actin cytoskeletons are aberrantly expressed in C9ALS cervical motor neurons. We also identified NNA1 and Smcr8 as novel interactors of C9, linking C9 to autophagy regulation. These results suggest that C9 repeat expansions, which deregulate posttranscriptional RNA processing, disturb the homeostasis of ECM and cytoskeletal dynamics, leading to neurodegeneration in C9ALS.

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