Intersectin 1 contributes to phenotypes in vivo: implications for Down's syndrome - PubMed (original) (raw)

Intersectin 1 contributes to phenotypes in vivo: implications for Down's syndrome

Michael P Hunter et al. Neuroreport. 2011.

Abstract

Intersectin 1 (ITSN1) is a human chromosome 21 (HSA21) gene product encoding a multidomain scaffold protein that functions in endocytosis, signal transduction, and is implicated in Down's syndrome, Alzheimer's Disease, and potentially other neurodegenerative diseases through activation of c-Jun N-terminal kinase. We report for the first time that ITSN1 proteins are elevated in individuals with Down's syndrome of varying ages. However, ITSN1 levels decreased in aged cases with Down's syndrome with Alzheimer's disease-like neuropathology. Analysis of a novel ITSN1 transgenic mouse reveals that ITSN1 overexpression results in a sex-dependent decrease in locomotor activity. This study reveals a link between overexpression of specific ITSN1 isoforms and behavioral phenotypes and has implications for human neurodegenerative diseases such as Down's syndrome and Alzheimer's disease.

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Figures

Figure 1

Figure 1. Expression of ITSN1 in human frontal cortex samples

(A) Relative expression of ITSN1-S and ITSN1-L was compared among all the samples. Difference in ITSN1-S levels between normal and Down Syndrome was statistically significant (p=0.023) using a Students t-test of the mean assuming unequal variance. (B) Relative expression of ITSN1 isoforms upon stratification of samples by genotype and age. Both control and Down Syndrome samples were segregated into below 40 or 40 yrs old and older. Bars represent standard error. Statistically significant differences in ITSN1-S and ITSN1-L (p=0.021 and p=0.035, respectively) in the younger Down Syndrome groupings compared to younger controls are marked, *. These differences were lost in the older Down Syndrome grouping. (C) Samples were stratified into control, Down Syndrome, Down Syndrome with diagnosed Alzheimer’s Disease neuropathology (Down Syndrome+Alzheimer’s Disease). Bars represent standard error. The difference in ITSN1-S and ITSN1-L levels in Down Syndrome (p=0.01 and p=0.026, respectively) vs control samples was statistically significant, *. As indicated in (C), these differences in ITSN1 levels were lost in the older Down Syndrome+Alzheimer’s Disease grouping. This decrease in ITSN1 levels in Down Syndrome+Alzheimer’s Disease samples vs Down Syndrome was statistically significant (**, p=0.026 for ITSN1-S; p=0.015 for ITSN1-L). Students t-test of the mean assuming unequal variance was used to calculate p values in A–C.

Figure 2

Figure 2. Expression of HA-tagged ITSN1 in brain regions of CaMKII-ITSN1 mice

(A) Top panels, HA-ITSN1 expression in the different brain regions of transgenics. Single transgenic control do not express HA-ITSN1. Middle panels, expression of endogenous ITSN1. Bottom panels, tubulin as a loading control. (B) Expression of ITSN1-L and ITSN1-S in the striatums of single transgenic controls and CaMKII-ITSN1 transgenic mice. ITSN1-L predominates in the controls, but ITSN1-S predominates in the CaMKII-ITSN1. Tubulin was used as a loading control. (C) The ratio of ITSN1-S to ITSN1-L levels in the striatums was determined from blots in (B) using NIH ImageJ. The differences in ratios were significant (p=0.022)

Figure 3

Figure 3. Reduced activity of CaMKII-ITSN1 mice

Results shown are for activity measurements during a 10 minute observation period. Male CaMKII-ITSN1 mice show reduced (A) horizontal activity (measurement of the movement of the animal in the horizontal plane of the open field chamber); (B) center distance (the total distance an animal travels in center of open field which measures exploratory behavior); (C) stereotypy time (time the animal spends in stereotypic activity such as grooming or head bobbing); and (D) stereotypy counts (the number of beam breaks that occur during stereotypic activity) compared to male single transgenic controls. Differences between CaMKII-ITSN1 and single transgenics were statistically significant for all four measures using Students t-test of the mean assuming unequal variance (P<0.05). Error bars show SEM. The following numbers of animals and average ages were used for this analysis: CaMKII-ITSN1: 9 M, 7.5+/−0.71 (SD) months; CaMKII: 9 M, 8.4+/−0.58 (SD) months; ITSN1: 10 M, 7.1+/−0.95 (SD) months.

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