Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Lien Nguyen, Fabio Montrasio, Amrutha Pattamatta, Solaleh Khoramian Tusi, Olgert Bardhi, Kevin D. Meyer, Lindsey Hayes, Katsuya Nakamura, Monica Banez-Coronel, Alyssa Coyne, Shu Guo, Lauren A. Laboissonniere, Yuanzheng Gu, Saravanakumar Narayanan, Benjamin Smith, Roger M. Nitsch, Mark W. Kankel, Mia Rushe, Jeffrey Rothstein, Tao ZuJan Grimm, Laura P.W. Ranum

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

Original languageEnglish (US)
Pages (from-to)645-662.e11
Issue number4
StatePublished - Feb 19 2020


  • BAC transgenic mice
  • C9orf72 ALS/FTD
  • G4C2 repeat expansion
  • RAN proteins
  • human antibody
  • immunotherapy
  • microsatellite expansion
  • proteasome and autophagy
  • protein co-aggregation
  • repeat associated non-ATG (RAN) translation

ASJC Scopus subject areas

  • Neuroscience(all)


Dive into the research topics of 'Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model'. Together they form a unique fingerprint.

Cite this