Consequences of the ‘Legs at odd angles’ mutation within the motor protein dynein and its possible implications in neurological disease

Garrett, Caroline Alice (2012) Consequences of the ‘Legs at odd angles’ mutation within the motor protein dynein and its possible implications in neurological disease. Doctoral thesis (PhD), University of Sussex.

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Cytoplasmic dynein is a retrograde motor protein complex that carries cargo such as organelles and growth factors along microtubules from the cell periphery towards the peri-nuclear region.

The cytoplasmic dynein complex is centred around two homodimerised heavy chains, within which multiple mutations have been identified in human neurological diseases.

The ‘Legs at odd angles’ (Loa) mouse has a missense ‘T’ to ‘A’ point mutation in the cytoplasmic dynein heavy chain gene (Dync1h1), resulting in a phenylalanine to tyrosine substitution at position 580. Mice homozygous for this mutation die within 24 hours of birth whilst heterozygote’s manifest an age-related and progressive neurodegeneration.

Fixed and live-cell microscopy shows aberrant movement of endocytosed growth factors in Loa. Retrograde speed is reduced with a distinct lack of the fastest moving carriers. Moreover, the overall pattern of movement is altered with increased anterograde and side-steps occurring in Loa.

Impaired endosomal trafficking of growth factors for degradation prolongs the activation of extracellular signal related kinases 1 and 2 (ERK 1/2) and increases the expression of the immediate early gene c-Fos in mouse embryonic fibroblasts. Motor neurons also show increased levels c-Fos however this can be induced by starvation, indicating their enhanced susceptibility to stress.

The light chain (KLC) of dynein’s opposing motor - kinesin is one of many genes differentially expressed in Loa compared to wild-type. In addition, associations of KLC with the dynein complex is altered in Loa.

Similarities between human neurological diseases and Loa both at the organism and cellular level make Loa a valuable tool towards understanding cellular mechanisms fundamental to the process of disease. Through understanding comes advancement towards therapeutic targets to improve the lives of thousands of people worldwide.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Library Cataloguing
Date Deposited: 10 Dec 2012 15:04
Last Modified: 07 Sep 2015 15:14

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