| First Author | Nguyen L | Year | 2020 |
| Journal | Neuron | Volume | 105 |
| Issue | 4 | Pages | 645-662.e11 |
| PubMed ID | 31831332 | Mgi Jnum | J:325530 |
| Mgi Id | MGI:6727634 | Doi | 10.1016/j.neuron.2019.11.007 |
| Citation | Nguyen L, et al. (2020) Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron 105(4):645-662.e11 |
| abstractText | 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, alpha-GA1 interacts with TRIM21, and alpha-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, alpha-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 alpha-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. |
