TY - JOUR
T1 - Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model
AU - Nguyen, Lien
AU - Montrasio, Fabio
AU - Pattamatta, Amrutha
AU - Tusi, Solaleh Khoramian
AU - Bardhi, Olgert
AU - Meyer, Kevin D.
AU - Hayes, Lindsey
AU - Nakamura, Katsuya
AU - Banez-Coronel, Monica
AU - Coyne, Alyssa
AU - Guo, Shu
AU - Laboissonniere, Lauren A.
AU - Gu, Yuanzheng
AU - Narayanan, Saravanakumar
AU - Smith, Benjamin
AU - Nitsch, Roger M.
AU - Kankel, Mark W.
AU - Rushe, Mia
AU - Rothstein, Jeffrey
AU - Zu, Tao
AU - Grimm, Jan
AU - Ranum, Laura P.W.
N1 - Funding Information:
We thank N. Cavegn, P. Borter, and N. Glassl for technical assistance; Dr. Christoph Hock for blood samples; Dr. J. Ravits for tissue samples; D. Sareen, C. Svendsen, and the iPS team at Cedars-Sinai for guidance on iPS motor neuron differentiation; and X. Tang, W. Zhou, and Y. Huo for technical assistance for iPS maintenance and differentiation. We thank the National Institutes of Health ( RO1 NS098819 ), Target ALS , the ALS Association , the Packard Center , and the Muscular Dystrophy Association for support.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/2/19
Y1 - 2020/2/19
N2 - 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.
AB - 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.
KW - BAC transgenic mice
KW - C9orf72 ALS/FTD
KW - G4C2 repeat expansion
KW - RAN proteins
KW - human antibody
KW - immunotherapy
KW - microsatellite expansion
KW - proteasome and autophagy
KW - protein co-aggregation
KW - repeat associated non-ATG (RAN) translation
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U2 - 10.1016/j.neuron.2019.11.007
DO - 10.1016/j.neuron.2019.11.007
M3 - Article
C2 - 31831332
AN - SCOPUS:85079230002
SN - 0896-6273
VL - 105
SP - 645-662.e11
JO - Neuron
JF - Neuron
IS - 4
ER -