Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in <i>Drosophila melanogaster</i>

Abstract

Background/Aims: Transthyretin (TTR) is a prevalent plasma and cerebrospinal fluid protein associated with sporadic and heritable amyloidosis. TTR amyloidosis is linked to a vast number of mutations with varying phenotype, tissue distribution and age of onset. The most prevalent mutation associated with familial amyloidotic polyneuropathy (FAP) is the V30M mutation. Studies of transgenic mouse models of TTR V30M FAP have been hampered by variable phenotype, low disease penetrance, and slow onset. Methods/Results: To model TTR-associated amyloid disease in the Drosophila model system, transgenic Drosophila were generated, expressing wild-type (wt) TTR or TTR V30M, associated with sporadic senile systemic amyloidosis (SSA) and inherited FAP, respectively. We found that expression of FAP-associated TTR V30M mutant in the nervous system resulted in reduced lifespan and in reduced climbing ability indicating neurological impairment, whereas expression of TTR wt showed a milder phenotype. Congo red staining of the Drosophila brain shows positive amyloid binding in the aged TTR V30M flies. Extensive brain vacuole formation was evident for the aged TTR V30M flies, whereas a milder phenotype was shown by the TTR wt flies. In addition, expression of TTR V30M in the eye leads to tissue damage, including rough eye, morphological changes and fibrous deposition. Conclusion: Our results suggest that Drosophila is a promising complementary system for studies of TTR-associated amyloid diseases.

Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila

“…The T 1/2 for all genotypes and curcumin concentrations are summarized in Table S1. The results from the longevity assay were essentially mirrored in a conventional climbing assay with a reduced climbing shifted of 1–2 days prior to death (Figure S1) as reported in previous studies [30].…”

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

“…When the amyloid protein transthyretin (TTR) was expressed in the photoreceptors this reduced the survival of the files [30]. In addition, TTR expression lead to a distortion of the eye morphology [30], a finding also reported by Berg et al [29] and by Crowther et al after Aβ expression driven to the same cellular location [41]. We have looked for morphological changes of the eye structure after hproIAPP expression, but neither TEM analysis of ommatidia nor SEM analysis of external eye structure showed any morphological deviations.…”

“…We used Drosophila melanogaster as model system which is already established for several other amyloid related diseases, such as Alzheimer's disease [28], familial amyloidotic polyneuropathy (FAP) [29], [30], and the prion disease Gerstmann-Sträussler-Scheinker syndrome [31].…”

Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

“…In addition to providing information on the effect of albumin under physiological conditions, these in vivo data suggest that the analbuminemic V30M Tg rat may become an animal model of FAP. Although attempts have been made to establish animal models of FAP, [47][48][49] a suitable model is not yet available. Because FAP is an adult-onset disease and prolonged time may be required for developing TTR deposition, 50 the analbuminemic V30M Tg rat may be a useful tool for examining the effect of different treatments on amyloid fibril formation within a shorter time frame (9 months old).…”