Network organization of the huntingtin proteomic interactome in mammalian brain.
We used affinity-purification mass spectrometry to identify 747 candidate proteins that are complexed with Huntingtin (Htt) in distinct brain regions and ages in Huntington's disease (HD) and wild-type mouse brains. To gain a systems-level view of the Htt interactome, we applied Weighted Correlation Network Analysis to the entire proteomic data set to unveil a verifiable rank of Htt-correlated proteins and a network of Htt-interacting protein modules, with each module highlighting distinct aspects of Htt biology. Importantly, the Htt-containing module is highly enriched with proteins involved in 14-3-3 signaling, microtubule-based transport, and proteostasis. Top-ranked proteins in this module were validated as Htt interactors and genetic modifiers in an HD Drosophila model. Our study provides a compendium of spatiotemporal Htt-interacting proteins in the mammalian brain and presents an approach for analyzing proteomic interactome data sets to build in vivo protein networks in complex tissues, such as the brain.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA.
Dyna I
DI
Shirasaki
Erin R
ER
Greiner
Ismael
I
Al-Ramahi
Michelle
M
Gray
Pinmanee
P
Boontheung
Daniel H
DH
Geschwind
Juan
J
Botas
Giovanni
G
Coppola
Steve
S
Horvath
Joseph A
JA
Loo
X William
XW
Yang
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins