Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.
Rose
Claudia
C
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Menzies
Fiona M
FM
Renna
Maurizio
M
Acevedo-Arozena
Abraham
A
Corrochano
Silvia
S
Sadiq
Oana
O
Brown
Steve D
SD
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism* / Q000633:toxicity; D000077769:Rilmenidine; D045442:Rotarod Performance Test
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010080:Oxazoles; D010455:Peptides; C097188:polyglutamine; D000077769:Rilmenidine