دانلود رایگان مقاله زمینه ژنتیکی تغییر آمیلوئیدوز در مدل موش نوروپاتی ATTR

Abstract

Penetrance and age of onset of ATTRV30M amyloidotic neuropathy varies significantly among different populations. This variability has been attributed to both genetic and environmental modifiers. We studied the effect of genetic background on phenotype in two lines of transgenic mice bearing the same ATTRV30M transgene. Amyloid deposition, transthyretin (TTR), megalin, clusterin and disease markers of endoplasmic reticulum stress, the ubiquitin-proteasome system, apoptosis, and complement activation were assessed with WB and immunohistochemistry in donor and recipient tissue. Our results indicate that genetic background modulates amyloid deposition by influencing TTR handling in recipient tissue and may partly account for the marked variability in penetrance observed in various world populations.

4. Discussion

In the present study we examined the effects of different genetic backgrounds on amyloid deposition and various related molecular pathogenic markers in a transgenic model of ATTRV30M. Genetic background has previously been shown to affect the phenotype and severity of other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) [15–17]. Considering that the two lines of mice used in the current study bear the same mutation with regards to the disease-causing locus, our results suggest that genetic modifiers affect disease progression, or in this case, amyloid deposition. The two lines of mice used here were the TM 129 mice, which were on a pure 129
1/SvJ background and the TM129/BL6 mice were on a mixture of 129
1/SvJ and C57BL/6J backgrounds. The latter group was considered genetically quite distinct from the reference group, bearing in mind the number of generations used for interbreeding. We have confirmed, through real-time PCR, that all mice used in this study carried the same number of disease causing mutated human TTR transgenes (V30M) (Fig. 1A). Furthermore, employing reverse transcription real-time PCR, we were able to quantify the expression of hTTR in the liver, the main site of TTR production (Fig. 1B). Our results indicate that TTR production in liver cells was indeed equivalent in both lines of animals (Fig. 2C). Secretion efficiency is likely similar in both lines since the TTR mutation is the same and hepatic levels of BiP are also the same (Fig. 3A). Therefore, any differences in amyloid deposition in stomach are likely due to differences in recipient tissue handling of the amyloidogenic protein.