Quantitative Phosphoproteomics Reveals Extensive Protein Phosphorylation Dysregulation in the Cerebral Cortex of Huntington’s Disease Mice Prior to Onset of Symptoms

Mees, Isaline; Tran, Harvey; Roberts, Anne M.; Lago, Larissa; Li, Shanshan; Roberts, Blaine R; Hannan, Anthony J; Renoir, Thibault

doi:10.1007/s12035-021-02698-y

Cited by 18 publications

(20 citation statements)

References 60 publications

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“… 5–7 We have recently reported a protein phosphorylation dysregulation in the cortex of R6/1 Huntington’s disease male mice in standard-housing conditions, occurring primarily prior to motor-symptom onset. 8 Our findings were supported by previously published evidence that protein phosphorylation is dysregulated in other Huntington’s disease mouse models. 9–12 Protein phosphorylation, catalysed by kinases and hydrolysed by phosphatases, plays a crucial role in cellular signalling, making this molecular process a promising target for the development of new Huntington’s disease treatments.…”

Section: Introductionsupporting

confidence: 89%

“…This finding is in contrast to our recent study which found an increased tau phosphorylation in the cortex of 8-week-old R6/1 Huntington’s disease mice when housed in SH conditions. 8 However, this could reflect a potential beneficial effect of EE in Huntington’s disease mice, whereby EE could have a different effect on WT versus Huntington’s disease mice.…”

Section: Discussionmentioning

confidence: 99%

“…This was associated with minimal changes in protein expression. Following up on our previous findings revealing a phosphoproteome dysregulation occurring in the cortex of pre-symptomatic Huntington’s disease male mice, 8 the present study only investigated protein and phosphorylation changes in male mice. Additional proteomics and phosphoproteomics experiments using Huntington’s disease female brain samples remain to be conducted.…”

Section: Discussionmentioning

confidence: 99%

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Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment

Mees

Tran

et al. 2022

Brain Communications

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Huntington’s disease is a fatal autosomal dominant neurodegenerative disorder, characterized by neuronal cell loss, primarily in the striatum, cortex, and hippocampus, causing motor, cognitive, and psychiatric impairments. Unfortunately, no treatments are yet available to modify the progression of the disease. Recent evidence from Huntington’s disease mouse models suggests that protein phosphorylation (catalysed by kinases and hydrolysed by phosphatases) might be dysregulated, making this major posttranslational modification a potential area of interest to find novel therapeutic targets. Furthermore, environmental enrichment, used to model an active lifestyle in preclinical models, has been shown to alleviate Huntington’s disease-related motor and cognitive symptoms. However, the molecular mechanisms leading to these therapeutic effects are still largely unknown. In this study, we applied a phosphoproteomics approach combined with proteomic analyses on brain samples from pre-motor symptomatic R6/1 Huntington’s disease male mice and their wild-type littermates, after being housed either in environmental enrichment conditions, or in standard housing conditions from 4 to 8 weeks of age (n = 6 per group). We hypothesised that protein-phosphorylation dysregulations occur prior to motor onset in this mouse model, in two highly affected brain regions, the striatum and hippocampus. Furthermore, we hypothesised that these phosphoproteome alterations are rescued by environmental enrichment. When comparing 8-week-old Huntington’s disease mice and wild-type mice in standard housing conditions, our analysis revealed 229 differentially phosphorylated peptides in the striatum, compared to only 15 differentially phosphorylated peptides in the hippocampus (statistical thresholds fold discovery rate 0.05, fold change 1.5). At the same disease stage, minor differences were found in protein levels, with 24 and 22 proteins dysregulated in the striatum and hippocampus, respectively. Notably, we found no differences in striatal protein phosphorylation and protein expression when comparing Huntington’s disease mice and their wild-type littermates in enriched conditions. In the hippocampus, only four peptides were differentially phosphorylated between the two genotypes under enriched conditions, and 22 proteins were differentially expressed. Together, our data indicates that protein phosphorylation dysregulations occur in the striatum of Huntington’s disease mice, prior to motor symptoms, and that the kinases and phosphatases leading to these changes in protein phosphorylation might be viable drug targets to consider for this disorder. Furthermore, we show that an early environmental intervention was able to rescue the changes observed in protein expression and phosphorylation in the striatum of Huntington’s disease mice and might underlie the beneficial effects of environmental enrichment, thus identifying novel therapeutic targets.

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Section: Introductionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment

Mees

Tran

et al. 2022

Brain Communications

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“…Totally, 1649 phosphoproteins, 3286 phosphopeptides and 4075 phosphorylation sites were identified in our study (Table S6, ESI †), showing better enrichment efficiency of our nanocomposite than the commercial NTAbased IMAC or MOAC adsorbent materials. [37][38][39] Moreover, we found that 50.2% phosphoproteins contained only one, two or three phosphorylation sites (Fig. 7a), and 77%, 21% and 2% phosphorylation sites were at the amino acid residues of serine, threonine and tyrosine, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

Superhydrophilic nanocomposite adsorbents modified via nitrogen-rich phosphonate-functionalized ionic liquid linkers: enhanced phosphopeptide enrichment and phosphoproteome analysis of tau phosphorylation in the hippocampal lysate of Alzheimer's transgenic mice

et al. 2022

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“…3A and C (different lower bounds for nonadjusted P values in responders and nonresponders, or apparent flatlines in the P values, which are the results of changes only in the 3rd to 5th decimal place in the P values of the nonsignificantly regulated peptides, thus not being truly flat). Examples of apparent flatlines in the nonsignificant portion of the data are abundant in the literature reporting phosphoproteomic screenings [55][56][57] , which may be an inherent issue of this discovery technique but can also be seen in geneexpression volcano plots 58 .…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A

et al. 2022

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Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.

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Quantitative Phosphoproteomics Reveals Extensive Protein Phosphorylation Dysregulation in the Cerebral Cortex of Huntington’s Disease Mice Prior to Onset of Symptoms

Cited by 18 publications

References 60 publications

Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment

Phosphoproteomic dysregulation in Huntington’s disease mice is rescued by environmental enrichment

Superhydrophilic nanocomposite adsorbents modified via nitrogen-rich phosphonate-functionalized ionic liquid linkers: enhanced phosphopeptide enrichment and phosphoproteome analysis of tau phosphorylation in the hippocampal lysate of Alzheimer's transgenic mice

Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A

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