Identifying polyglutamine protein species in situ that best predict neurodegeneration.
Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Jason
J
Miller
Montserrat
M
Arrasate
Elizabeth
E
Brooks
Clare Peters
CP
Libeu
Justin
J
Legleiter
Danny
D
Hatters
Jessica
J
Curtis
Kenneth
K
Cheung
Preethi
P
Krishnan
Siddhartha
S
Mitra
Kartika
K
Widjaja
Benjamin A
BA
Shaby
Gregor P
GP
Lotz
Yvonne
Y
Newhouse
Emily J
EJ
Mitchell
Alex
A
Osmand
Michelle
M
Gray
Vanitha
V
Thulasiramin
Frédéric
F
Saudou
Mark
M
Segal
X William
XW
Yang
Eliezer
E
Masliah
Leslie M
LM
Thompson
Paul J
PJ
Muchowski
Karl H
KH
Weisgraber
Steven
S
Finkbeiner
D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry; D008970:Molecular Weight; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000633:toxicity*; D013329:Structure-Activity Relationship; D019680:Trinucleotide Repeat Expansion
D000911:Antibodies, Monoclonal; D000939:Epitopes; D010455:Peptides; C097188:polyglutamine