Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression

被引：71

作者：

Southwell, Amber L. ^{[1
,2
]}

Smith, Stephen E. P. ^{[3
]}

Davis, Tessa R. ^{[3
]}

Caron, Nicholas S. ^{[1
,2
]}

Villanueva, Erika B. ^{[1
,2
]}

Xie, Yuanyun ^{[1
,2
]}

Collins, Jennifer A. ^{[1
,2
]}

Ye, Min Li ^{[1
,2
]}

Sturrock, Aaron ^{[1
,2
]}

Leavitt, Blair R. ^{[1
,2
]}

Schrum, Adam G. ^{[3
]}

Hayden, Michael R. ^{[1
,2
]}

机构：

[1] Univ British Columbia, Child & Family Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada

[2] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4H4, Canada

[3] Mayo Clin, Coll Med, Dept Immunol, Rochester, MN 55905 USA

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

MUTANT HUNTINGTIN; EMBRYONIC LETHALITY; MOUSE MODEL; GENE; NEUROPATHOLOGY; REVERSAL; PROGRESSION; DISRUPTION; FRAGMENTS; REPEAT;

D O I：

10.1038/srep12166

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.

引用

页数：11

共 19 条

[1] Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression
Amber L. Southwell
Stephen E.P. Smith
Tessa R. Davis
Nicholas S. Caron
Erika B. Villanueva
Yuanyun Xie
Jennifer A. Collins
Min Li Ye
Aaron Sturrock
Blair R. Leavitt
Adam G. Schrum
Michael R. Hayden
Scientific Reports, 5
[2] Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice
Caron, Nicholas S.
Banos, Raul
Aly, Amirah E.
Xie, Yuanyun
Ko, Seunghyun
Potluri, Nalini
Anderson, Christine
Black, Hailey Findlay
Anderson, Lisa M.
Gordon, Benjamin
Southwell, Amber L.
Hayden, Michael R.
NEUROBIOLOGY OF DISEASE, 2022, 166
[3] Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients
Wild, Edward J.
Boggio, Roberto
Langbehn, Douglas
Robertson, Nicola
Haider, Salman
Miller, James R. C.
Zetterberg, Henrik
Leavitt, Blair R.
Kuhn, Rainer
Tabrizi, Sarah J.
Macdonald, Douglas
Weiss, Andreas
JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (05): : 1979 - 1986
[4] Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin
Z Tan
W Dai
T G M van Erp
J Overman
A Demuro
M A Digman
A Hatami
R Albay
E M Sontag
K T Potkin
S Ling
F Macciardi
W E Bunney
J D Long
J S Paulsen
J M Ringman
I Parker
C Glabe
L M Thompson
W Chiu
S G Potkin
Molecular Psychiatry, 2015, 20 : 1286 - 1293
[5] Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin
Tan, Z.
Dai, W.
van Erp, T. G. M.
Overman, J.
Demuro, A.
Digman, M. A.
Hatami, A.
Albay, R.
Sontag, E. M.
Potkin, K. T.
Ling, S.
Macciardi, F.
Bunney, W. E.
Long, J. D.
Paulsen, J. S.
Ringman, J. M.
Parker, I.
Glabe, C.
Thompson, L. M.
Chiu, W.
Potkin, S. G.
MOLECULAR PSYCHIATRY, 2015, 20 (11) : 1286 - 1293
[6] HAP40 protein levels are huntingtin-dependent and decrease in Huntington disease
Huang, Bin
Seefelder, Manuel
Buck, Eva
Engler, Tatjana
Lindenberg, Katrin S.
Klein, Fabrice
Landwehrmeyer, G. Bernhard
Kochanek, Stefan
NEUROBIOLOGY OF DISEASE, 2021, 158
[7] Sustained mutant Huntingtin lowering in the brain and cerebrospinal fluid of Huntington disease minipigs mediated by AAV5-miHTT gene therapy
Valles, A.
Brouwers, C.
Pintauro, R.
Snapper, J.
Bohuslavova, B.
Sogorb-Gonzalez, M.
Fodale, V.
Bresciani, A.
Ellederova, Z.
Blits, B.
Motlik, J.
van Deventer, S.
Evers, M.
Konstantinova, P.
HUMAN GENE THERAPY, 2018, 29 (12) : A82 - A82
[8] SUSTAINED MUTANT HUNTINGTIN LOWERING IN THE BRAIN AND CEREBROSPINAL FLUID OF HUNTINGTON DISEASE MINIPIGS MEDIATED BY AAV5-MIHTT GENE THERAPY
Valles, Astrid
Brouwers, Cynthia
Pintauro, Roberta
Snapper, Jolanda
Bohuslavova, Bozena
Sogorb-Gonzalez, Marina
Fodale, Valentina
Bresciani, Alberto
Ellederova, Zdenka
Blits, Bas
Motlik, Jan
van Deventer, Sander
Evers, Melvin
Konstantinova, Paylina
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2018, 89 : A89 - A90
[9] Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of Huntington disease minipigs mediated by AAV5-miHTT gene therapy
Valles-Sanchez, A.
Stam, A.
Brouwers, C.
Klima, J.
Bohuslavova, B.
Pintauro, R.
Sogorb-Gonzalez, M.
Paerels, L.
Fodale, V.
Bresciani, A.
Ellederova, Z.
Blits, B.
Motlik, J.
van Deventer, S.
Evers, M.
Konstantinova, P.
MOVEMENT DISORDERS, 2019, 34 : S22 - S22
[10] Detection of high levels of mutant huntingtin protein in tear fluid of patients with Huntington's Disease
Gijs, Marlies
Jorna, Nynke
Datson, Nicole
Beekman, Chantal
Dansokho, Cira
Weiss, Alexander
Linden, David
Oosterloo, Mayke
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2024, 65 (07)

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