Formation of polyglutamine inclusions in non-CNS tissue.
Huntington's disease (HD) is one of a class of inherited progressive neurodegenerative disorders that are caused by a CAG/polyglutamine repeat expansion. We have previously generated mice that are transgenic for exon 1 of the HD gene carrying highly expanded CAG repeats which develop a progressive movement disorder and weight loss with similarities to HD. Neuronal inclusions composed of the exon 1 protein and ubiquitin are present in specific brain regions prior to onset of the phenotype, which in turn occurs long before specific neurodegeneration can be detected. In this report we have extended the search for polyglutamine inclusions to non-neuronal tissues. Outside the central nervous system (CNS), inclusions were identified in a variety of post-mitotic cells. This is consistent with a concentration-dependent nucleation and aggregation model of inclusion formation and indicates that brain-specific factors are not necessary for this process. To possibly gain insights into the wasting that is observed in the human disease, we have conducted a detailed analysis of the timing and progression of inclusion formation in skeletal muscle and an investigation into the cause of the severe muscle atrophy that occurs in the mouse model. The formation of inclusions in non-CNS tissues will be particularly useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.
Sathasivam
K
K
Medical and Molecular Genetics, GKT Medical and Dental School, King's College, 8th Floor, Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
Hobbs
C
C
Turmaine
M
M
Mangiarini
L
L
Mahal
A
A
Bertaux
F
F
Wanker
E E
EE
Doherty
P
P
Davies
S W
SW
Bates
G P
GP
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000648:ultrastructure; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure*; D009133:Muscular Atrophy / Q000235:genetics* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics*
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine