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Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in Drosophila melanogaster
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0001-5095-541X
Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.ORCID-id: 0000-0001-5827-3587
2009 (engelsk)Inngår i: NEURODEGENERATIVE DISEASES, ISSN 1660-2854, Vol. 6, nr 3, s. 127-138Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2009. Vol. 6, nr 3, s. 127-138
Emneord [en]
Amyloid disease, Drosophila melanogaster, Transthyretin, Familial amyloidotic polyneuropathy
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-18382DOI: 10.1159/000213761OAI: oai:DiVA.org:liu-18382DiVA, id: diva2:218870
Tilgjengelig fra: 2009-05-25 Laget: 2009-05-25 Sist oppdatert: 2018-04-25
Inngår i avhandling
1. Modeling Amyloid Disease in Drosophila melanogaster
Åpne denne publikasjonen i ny fane eller vindu >>Modeling Amyloid Disease in Drosophila melanogaster
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Amyloid diseases are caused by protein misfolding and aggregation. To date there are 27 known proteins causing amyloid disorders involving brain and peripheral protein deposition. The proteins involved in this mechanism do not share sequence homology, but the amyloid fibrils share biophysical properties and possibly a common pathogenic mechanism. Amyloid deposits are known to be involved in a broad range of neurodegenerative diseases, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, as well as in non-neuropathic diseases, such as senile systemic amyloidosis and type II diabetes.

During the last decade the fruit fly, Drosophila melanogaster (Drosophila), have increasingly been used as a model for neurodegenerative disease, such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and familial amyloidotic polyneuropathy. The advantages of using the Drosophila model are the well-defined genetic characteristics, the quantity, short life span, simplicity in genetic manipulation and the powerful binary UAS-Gal4 transgenic system. The UAS-Gal4 system allows for rapid generation of individual strains in which expression of a specific gene of interest can be directed to different tissues or cell types. The system allows the target gene to be activated in different cell- and tissue-types by altering the activator-expressing lines.

This thesis has been focused on modeling amyloid diseases in Drosophila. This has been performed by:

  • Creating new model systems of senile systemic amyloidosis and familial amyloidotic polyneuropathy in Drosophila
  • Developing a new staining protocol for detection of amyloid in Drosophila
  • Initiate a compound screen of Alzheimer’s disease modeled in Drosophila
sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2010. s. 88
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1320
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-55025 (URN)978-91-7393-379-7 (ISBN)
Disputas
2010-05-21, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2010-04-27 Laget: 2010-04-27 Sist oppdatert: 2018-04-25bibliografisk kontrollert

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