PXD005138

PXD005138 is an original dataset announced via ProteomeXchange.

Title	Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models
Description	Using Huntington’s disease (HD) mouse models that quantitatively replicate the reduction of striatal Phoshodiesterase 10 (PDE10) levels in manifest Huntington’s disease patients, we demonstrate the potential therapeutic benefit of PDE10 inhibition on correcting basal ganglia circuitry deficits thought to drive disease symptomology in patients. PDE10 inhibition acutely restored corticostriatal input and boosted cortically driven indirect pathway activity in HD models with compromised PDE10 levels. We show that cyclic nucleotide signaling processes are impaired in the models, and that elevation of both the cAMP and cGMP nucleotides afforded by PDE10 inhibition are required for this rescue. Global phosphoproteomic profiling of striatal proteins in response to PDE10 inhibition provide novel information on the plausible neural substrates responsible for the improvement. Finally, we show that long-term chronic treatment of the Q175 knock-in mouse model with PDE10A inhibitors, starting at a presymptomatic age, showed improvements, above and beyond those seen during acute administration, including a partial reversal of striatal deregulated transcripts predominantly driven through activation of the AP-1 and CREB transcription factor complexes, and a prevention of the emergence of some cardinal HD neurophysiological deficits.
HostingRepository	PRIDE
AnnounceDate	2017-10-24
AnnouncementXML	Submission_2017-10-24_02:00:42.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Manuela Machatti
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2016-10-12 23:43:50	ID requested
1	2016-12-05 00:25:17	announced
2	2016-12-14 02:30:54	announced	Updated publication reference for PubMed record(s): 27916455.
⏵ 3	2017-10-24 02:00:43	announced	Updated project metadata.

Beaumont V, Zhong S, Lin H, Xu W, Bradaia A, Steidl E, Gleyzes M, Wadel K, Buisson B, Padovan-Neto FE, Chakroborty S, Ward KM, Harms JF, Beltran J, Kwan M, Ghavami A, H, ä, ggkvist J, T, ó, th M, Halldin C, Varrone A, Schaab C, Dybowski JN, Elschenbroich S, Lehtim, ä, ki K, Heikkinen T, Park L, Rosinski J, Mrzljak L, Lavery D, West AR, Schmidt CJ, Zaleska MM, Munoz-Sanjuan I, Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. Neuron, 92(6):1220-1237(2016) [pubmed]

curator keyword: Biomedical

submitter keyword: Huntington's disease

Proteomics

Phosphoproteomics;PDE10A;Striatum;

Christoph Schaab
contact affiliation	Evotec
contact email	christoph.schaab@evotec.com
lab head
Manuela Machatti
contact affiliation	Evotec
contact email	manuela.machatti@evotec.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD005138

PRIDE project URI

• PRIDE
  1. PXD005138
     1. Label: PRIDE project
     2. Name: Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington’s disease models