Author: Dorothee Angelique Gaelle Girard
Girard, Dorothee Angelique Gaelle, 2013 In-depth characterisation of the Alms1foz/foz mouse model of Alstrom syndrome, Flinders University, School of Medicine
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Monogenic causes of obesity and type 2 diabetes mellitus (T2DM) include Alstrom syndrome (AS). AS belongs to an interesting new class of disorders called ciliopathies, which have a common origin in gene mutations causing dysfunction of an important cellular organelle known as the primary cilium. AS is inherited as an autosomal recessive disorder caused by a mutation in the ALMS1 gene that leads to an extensive clinical phenotype encompassing childhood metabolic disorders, retinal degeneration, sensorineural deafness, cardiomyopathy and infertility. Thus, research into ciliopathies including AS represents an exciting novel focus in a wide range of research fields including endocrinology and neurosciences. The 'Fat Aussie' (FA) mouse or Alms1foz/foz is a model for AS that carries a spontaneous deletion (foz) in the exon 8 of the ALMS1 gene. The Alms1foz/foz mouse recapitulates the disorders occurring in AS patients and represents a unique opportunity to further characterise the pathogenic mechanisms underlying ciliopathy-associated obesity, insulin resistance and T2DM. The metabolic phenotyping study of Alms1foz/foz mice has revealed that early peripheral insulin resistance is an inherent primary consequence of the ALMS1 gene disruption at a time that Beta-cell function isn't affected. Insulin resistance may thereby drive the subsequent metabolic complications in the Alms1foz/foz mouse model. Outcomes from this study also suggest that the defect leading to insulin resistance in Alms1foz/foz mice must be downstream of AS160 phosphorylation in the insulin pathway and might concern either the translocation of GLUT4 or its recycling. Female NOD/Alms1foz/foz mice were then used as a new model to investigate the intricate relationship between metabolic disturbances such as obesity and T2DM and the onset of type 1 diabetes mellitus (T1DM). Surprisingly, NOD/Alms1foz/foz mice were protected against T1DM. Data showed that beta cell destruction was significantly suppressed in NOD/Alms1foz/foz mice which had intact hyperplastic beta-islets, limited immune cell infiltration and unaltered insulin secretory capacity. Thus, metabolic disturbances in NOD/Alms1foz/foz mice may paradoxically inhibit the development of T1DM. New features, which have not been described before in AS mouse models, have been highlighted in this project. Alms1foz/foz mice displayed early mild cognitive impairment worsening with age suggesting defective neuronal function. The axonal transport of Alms1 protein further suggests a possible involvement of Alms1 in neuronal protein trafficking. Neuroendocrine chromaffin cells from Alms1foz/foz mice showed a reduced exocytosis rate but unimpaired pore fusion kinetics. Together, these data suggest a possible involvement of the Alms1 protein in neuronal signalling and vesicle trafficking. This project has helped to better characterise the underlying defects that drive the FA mouse model of AS to multi-organ pathology by finding clues to Alms1 protein function. Research into unravelling Alms1 protein function should not only lead to improved treatments for patients with AS, but also provide a better understanding of cellular pathways involved in more common disorders such as obesity and T2DM.
Keywords: Alstrom syndrome,metabolic disorders,Alms1foz/foz mouse model
Subject: Endocrinology thesis
Thesis type: Doctor of Philosophy
School: School of Medicine
Supervisor: Prof Nikolai Petrovsky