MicroRNA pathways modulate polyglutamine-induced neurodegeneration.
Nine human neurodegenerative diseases are due to expansion of a CAG repeat- encoding glutamine within the open reading frame of the respective genes. Polyglutamine (polyQ) expansion confers dominant toxicity, resulting in neuronal degeneration. MicroRNAs (miRNAs) have been shown to modulate programmed cell death during development. To address whether miRNA pathways play a role in neurodegeneration, we tested whether genes critical for miRNA processing modulated toxicity induced by the spinocerebellar ataxia type 3 (SCA3) protein. These studies revealed a striking enhancement of polyQ toxicity upon reduction of miRNA processing in Drosophila and human cells. In parallel genetic screens, we identified the miRNA bantam (ban) as a potent modulator of both polyQ and tau toxicity in flies. Our studies suggest that ban functions downstream of toxicity of the SCA3 protein, to prevent degeneration. These findings indicate that miRNA pathways dramatically modulate polyQ- and tau-induced neurodegeneration, providing the foundation for new insight into therapeutics.
Bilen
Julide
J
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Liu
Nan
N
Burnett
Barrington G
BG
Pittman
Randall N
RN
Bonini
Nancy M
NM
D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D000067699:Ataxin-3; D016213:Cyclins / Q000502:physiology; D004247:DNA / Q000737:chemistry; D004330:Drosophila / Q000033:anatomy & histology / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016366:Open Reading Frames; D010455:Peptides / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000033:anatomy & histology; D019680:Trinucleotide Repeat Expansion; D016875:tau Proteins / Q000378:metabolism
D016213:Cyclins; D029721:Drosophila Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; C471146:bantam microRNA, Drosophila; D016875:tau Proteins; C097188:polyglutamine; D004247:DNA; C092341:ATXN3 protein, human; D000067699:Ataxin-3