Rescue of mutant rhodopsin traffic by metformin-induced AMPK activation accelerates photoreceptor degeneration.
Hum Mol Genet
; 26(2): 305-319, 2017 01 15.
Article
in En
| MEDLINE
| ID: mdl-28065882
ABSTRACT
Protein misfolding caused by inherited mutations leads to loss of protein function and potentially toxic 'gain of function', such as the dominant P23H rhodopsin mutation that causes retinitis pigmentosa (RP). Here, we tested whether the AMPK activator metformin could affect the P23H rhodopsin synthesis and folding. In cell models, metformin treatment improved P23H rhodopsin folding and traffic. In animal models of P23H RP, metformin treatment successfully enhanced P23H traffic to the rod outer segment, but this led to reduced photoreceptor function and increased photoreceptor cell death. The metformin-rescued P23H rhodopsin was still intrinsically unstable and led to increased structural instability of the rod outer segments. These data suggest that improving the traffic of misfolding rhodopsin mutants is unlikely to be a practical therapy, because of their intrinsic instability and long half-life in the outer segment, but also highlights the potential of altering translation through AMPK to improve protein function in other protein misfolding diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Retinal Degeneration
/
Rhodopsin
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Retinitis Pigmentosa
/
AMP-Activated Protein Kinases
/
Metformin
Limits:
Animals
/
Humans
Language:
En
Journal:
Hum Mol Genet
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2017
Type:
Article
Affiliation country:
United kingdom