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Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β -amyloid burden and synaptic deficits in Lewy body dementias

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ABSTRACT

Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson’s disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.

Electronic supplementary material: The online version of this article (doi:10.1186/s13041-016-0264-9) contains supplementary material, which is available to authorized users.

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Increased pThr514 CRMP2 correlates with synaptophysin loss in in LBD parietal cortex. a Bar graph of synaptophysin immunoreactivity (mean ± SEM in arbitrary units) and representative immunoblots, with GAPDH as loading control. Scatter plots of pThr514 CRMP2 with synaptophysin immunoreactivities in total homogenate fractions of b LBD (DLB + PDD), c DLB and d PDD parietal cortex, with insets indicating rho and p values. Where a correlation is significant, a best-fit regression line (solid line) is added together with its 95 % prediction intervals (dotted lines). Available N for control (C) = 19; PDD (P) = 19 and DLB (D) = 20. §p < 0.05, significant difference for multiple pair-wise comparisons (one-way ANOVA with Bonferroni post-hoc tests). *p < 0.05, significant Spearman correlations
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Fig4: Increased pThr514 CRMP2 correlates with synaptophysin loss in in LBD parietal cortex. a Bar graph of synaptophysin immunoreactivity (mean ± SEM in arbitrary units) and representative immunoblots, with GAPDH as loading control. Scatter plots of pThr514 CRMP2 with synaptophysin immunoreactivities in total homogenate fractions of b LBD (DLB + PDD), c DLB and d PDD parietal cortex, with insets indicating rho and p values. Where a correlation is significant, a best-fit regression line (solid line) is added together with its 95 % prediction intervals (dotted lines). Available N for control (C) = 19; PDD (P) = 19 and DLB (D) = 20. §p < 0.05, significant difference for multiple pair-wise comparisons (one-way ANOVA with Bonferroni post-hoc tests). *p < 0.05, significant Spearman correlations

Mentions: CRMP2 phosphorylation, including pThr514, is known to deactivate CRMP2 and affect axonal growth cone as well as associated synaptic function and plasticity [10, 34, 35]. To study possible synaptic effects of increased pThr514 CRMP2, we correlated pThr514 immunoreactivity with markers of regenerating axon/growth cone (β-III-tubulin [36, 37]) and synaptic integrity (synaptophysin [38]). Both β-III-tubulin and synaptophysin were decreased in DLB, with intermediate values in PDD (Figs. 3a and 4a). These results indicate the presence of synaptic deficits in LBD, especially with concomitant Aβ burden. Interestingly, pThr514 CRMP2 negatively correlated with both β-III-tubulin and synaptophysin in LBD (Figs. 3b and 4b), although for β-III-tubulin the correlations were not significant within the dementia subgroups (Fig. 3c and d), while correlations remained significant in DLB, but not PDD, in the case of synaptophysin (Fig. 4c and d). Taken together, the data suggest that increased pThr514 CRMP2 is associated with deficits in axonal regeneration and synaptic integrity in LBD.Fig. 3


Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β -amyloid burden and synaptic deficits in Lewy body dementias
Increased pThr514 CRMP2 correlates with synaptophysin loss in in LBD parietal cortex. a Bar graph of synaptophysin immunoreactivity (mean ± SEM in arbitrary units) and representative immunoblots, with GAPDH as loading control. Scatter plots of pThr514 CRMP2 with synaptophysin immunoreactivities in total homogenate fractions of b LBD (DLB + PDD), c DLB and d PDD parietal cortex, with insets indicating rho and p values. Where a correlation is significant, a best-fit regression line (solid line) is added together with its 95 % prediction intervals (dotted lines). Available N for control (C) = 19; PDD (P) = 19 and DLB (D) = 20. §p < 0.05, significant difference for multiple pair-wise comparisons (one-way ANOVA with Bonferroni post-hoc tests). *p < 0.05, significant Spearman correlations
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Fig4: Increased pThr514 CRMP2 correlates with synaptophysin loss in in LBD parietal cortex. a Bar graph of synaptophysin immunoreactivity (mean ± SEM in arbitrary units) and representative immunoblots, with GAPDH as loading control. Scatter plots of pThr514 CRMP2 with synaptophysin immunoreactivities in total homogenate fractions of b LBD (DLB + PDD), c DLB and d PDD parietal cortex, with insets indicating rho and p values. Where a correlation is significant, a best-fit regression line (solid line) is added together with its 95 % prediction intervals (dotted lines). Available N for control (C) = 19; PDD (P) = 19 and DLB (D) = 20. §p < 0.05, significant difference for multiple pair-wise comparisons (one-way ANOVA with Bonferroni post-hoc tests). *p < 0.05, significant Spearman correlations
Mentions: CRMP2 phosphorylation, including pThr514, is known to deactivate CRMP2 and affect axonal growth cone as well as associated synaptic function and plasticity [10, 34, 35]. To study possible synaptic effects of increased pThr514 CRMP2, we correlated pThr514 immunoreactivity with markers of regenerating axon/growth cone (β-III-tubulin [36, 37]) and synaptic integrity (synaptophysin [38]). Both β-III-tubulin and synaptophysin were decreased in DLB, with intermediate values in PDD (Figs. 3a and 4a). These results indicate the presence of synaptic deficits in LBD, especially with concomitant Aβ burden. Interestingly, pThr514 CRMP2 negatively correlated with both β-III-tubulin and synaptophysin in LBD (Figs. 3b and 4b), although for β-III-tubulin the correlations were not significant within the dementia subgroups (Fig. 3c and d), while correlations remained significant in DLB, but not PDD, in the case of synaptophysin (Fig. 4c and d). Taken together, the data suggest that increased pThr514 CRMP2 is associated with deficits in axonal regeneration and synaptic integrity in LBD.Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of &beta;-amyloid (A&beta;), tau-phosphorylation, &alpha;-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson&rsquo;s disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic A&beta; as well as with losses of markers for axon regeneration (&beta;-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or &alpha;-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3&beta; and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with A&beta; and other neuropathologic markers require further study.

Electronic supplementary material: The online version of this article (doi:10.1186/s13041-016-0264-9) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus