Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit.
Nat Neurosci
; 24(7): 930-940, 2021 07.
Article
in En
| MEDLINE
| ID: mdl-33795885
ABSTRACT
The neurodegenerative disease spinal muscular atrophy (SMA) is caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for SMN expression beyond physiological levels is a unique feature of adeno-associated virus serotype 9 (AAV9)-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins, leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and the innate immune response. Thus, long-term SMN overexpression interferes with RNA regulation and triggers SMA-like pathogenic events through toxic gain-of-function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities warrant caution on the long-term safety of treating individuals with SMA with AAV9-SMN and the risks of uncontrolled protein expression by gene therapy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Survival of Motor Neuron 1 Protein
/
Motor Neurons
/
Nerve Degeneration
Limits:
Animals
Language:
En
Journal:
Nat Neurosci
Journal subject:
NEUROLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Estados Unidos