β-cell dysfunction in Huntington's disease
Författare
Summary, in English
Upon characterization of the R6/2 mouse model we found that mutant huntingtin renders β-cells replication-deficient. This results in a reduced β-cell mass in R6/2 compared to WT mice. In addition, islet insulin content is reduced and a dramatic degranulation of β-cells is evident. As a consequence, insulin secretion is severely blunted and R6/2 mice become glucose intolerant. In our present studies we could, however, not find any morphological alterations in pancreatic sections from HD patients. Thus, what pathogenetic defects that underlie the secretory deficiency evident in HD patients remain to be resolved. In an effort to identify such defects we created an in vitro model of the HD β-cell and found that glucose-stimulated insulin secretion is significantly blunted by mutant huntingtin. Because metabolic perturbations have been identified in HD and are a possible cause of the secretory defect, we investigated cellular metabolism. However, we found glucose oxidation and mitochondrial respiration, as well as expression levels of metabolic enzymes, unaltered. This suggests that metabolic aberrations do not contribute to cell dysfunction in our model. Next we analyzed vesicular trafficking as this has been found aberrant in HD and is vital for sustained insulin release. These studies showed that the transport of insulin granules along microtubule filaments is perturbed. Furthermore, we found that mutant huntingtin interacts aberrantly with β-tubulin. Therefore we hypothesize that mutant huntingtin acts as a physical block for vesicular transport. This mechanism is likely not specific for β-cells and might therefore contribute to the trafficking defects seen in neurons. Thus, attenuating the huntingtin/β-tubulin interaction may have beneficial effects in HD patients.
Publiceringsår
2009
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University Faculty of Medicine Doctoral Dissertation Series
Volym
2009:49
Fulltext
Dokumenttyp
Doktorsavhandling
Förlag
Department of Clinical Sciences, Lund University
Ämne
- Endocrinology and Diabetes
Nyckelord
- metabolism
- secretion
- Insulin
- trafficking
- R6/2 mouse
- granule
- exocytosis
- neurodegeneration
- huntingtin
Status
Published
Handledare
- Hindrik Mulder
- Patrik Brundin
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-86253-37-0
Försvarsdatum
8 maj 2009
Försvarstid
13:00
Försvarsplats
Segerfalk lecture hall, Wallenberg Neuroscience Center, BMC, Sölvegatan 19, Lund
Opponent
- Neil Aronin (Professor)