Dataset Information

PTMs of HTT protein - Post-translational modifications (PTMs), identified on endogenous huntingtin, cluster within proteolytic domains between HEAT repeats

ABSTRACT: Post-translational modifications (PTMs) of proteins regulate various cellular processes. PTMs of polyglutamine-expanded huntingtin (Htt) protein, causative of Huntington’s disease (HD), are likely modulators of HD pathogenesis. Previous studies have identified and characterized several PTMs on exogenously expressed Htt fragments, however none of these studies were designed to systematically characterize PTMs on the endogenous full-length Htt protein.We found that full-length endogenous Htt, immunoprecipitated from HD knock-in mouse and human post mortem brain, is suitable for detection of PTMs by mass spectrometry. Using label-free mass spectrometry, we identified around 40 PTMs, of which half are novel. These findings will be instrumental in the further assembling the Htt PTM framework, and validate PTMs of Htt as promising therapeutic targets for HD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Huntington Disease

SUBMITTER: Tamara Ratovitski

LAB HEAD: Christopher A. Ross

PROVIDER: PXD005753 | Pride | 2017-06-29

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	120507_RossC_RT_TiO2_1B.mgf	Mgf
	120507_RossC_RT_TiO2_1B.pride.mgf.gz	Mgf
	120507_RossC_RT_TiO2_1B.raw	Raw
	120507_RossC_RT_TiO2_2AB.mgf	Mgf
	120507_RossC_RT_TiO2_2AB.pride.mgf.gz	Mgf

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Publications

Post-Translational Modifications (PTMs), Identified on Endogenous Huntingtin, Cluster within Proteolytic Domains between HEAT Repeats.

Ratovitski Tamara T O'Meally Robert N RN Jiang Mali M Chaerkady Raghothama R Chighladze Ekaterine E Stewart Jacqueline C JC Wang Xiaofang X Arbez Nicolas N Roby Elaine E Alexandris Athanasios A Duan Wenzhen W Vijayvargia Ravi R Seong Ihn Sik IS Lavery Daniel J DJ Cole Robert N RN Ross Christopher A CA

Journal of proteome research 20170703 8

Post-translational modifications (PTMs) of proteins regulate various cellular processes. PTMs of polyglutamine-expanded huntingtin (Htt) protein, which causes Huntington's disease (HD), are likely modulators of HD pathogenesis. Previous studies have identified and characterized several PTMs on exogenously expressed Htt fragments, but none of them were designed to systematically characterize PTMs on the endogenous full-length Htt protein. We found that full-length endogenous Htt, which was immuno ...[more]

PMID: 28653853

Publication: 1/2

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Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.