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• W183359539 abstract "Cytoskeletal protein abnormalities are common features of a number ofneurodegenerative conditions. However, the potential roles of neurofilaments (NFs)in neurodegenerative disease and in ageing-related cellular changes are poorlyunderstood. Many models of NF abnormalities in mice have been reported, but howageing affects the NF pathology and the role of ageing in neurodegenerative diseasesare still unknown. This thesis, therefore, sought to examine the effects of the absenceof a major class of NF proteins, in NF light (NF-L) knockout (KO) mice, on theageing-related adaptive capacity of other cytoskeletal elements in neurons, and alsoon neurodegeneration-linked alteration of cytoskeletal proteins, cytoskeletal RNAbindingproteins (TDP-43) and myelin proteins.The NF-L subunit is considered as an obligate subunit polymer for the assembly ofNF triplet proteins into neuronal intermediate filaments (IFs). Previous studies haveshown that NF-L KO mice have substantially reduced axonal intermediate filaments.NF abnormalities such as NF accumulation, reduced NF-L mRNA, and NFmutations have been described in human neurodegenerative disease.This thesis has used immunohistochemical and quantitative Western blot techniquesto examine cytoskeletal changes in the brains of NF-L KO and wild-type (WT) miceat different ages. It was demonstrated that depletion of NF-L protein resulted inalteration of the expression of a range of cytoskeletal proteins, and disrupts otherneuronal IF proteins, through ageing. However, there were no gross structural changes in neurons or cytoarchitecture in regions such as the cerebral cortex. In thisregard, alterations in the expression of other cytoskeletal proteins may compensatefor decreased NFs.TDP-43, an NF-L mRNA binding protein, has recently been pathologicallyassociated with a number of neurodegenerative diseases of ageing. However,mechanisms of TDP-43 pathogenesis are unknown. As TDP-43 is known to bind toNF-L mRNA, this thesis used immunohistochemical and quantitative Western blotapproaches to characterize and quantify the changes of TDP-43 expression anddistribution in brain and spinal cord of ageing NF-L KO mice as compared to WTanimals. It was found that a significant increase of TDP-43 protein levels occurred inthe cortex and lumbar spinal cord in NF-L KO mice at 12 months of age, comparedto WT mice. Moreover, an increase of phosphorylated TDP-43 was found in thecervical spinal cord of NF-L KO mice at 12 months, compared to WT controls.NFs have a critical role in myelination by regulating axonal diameter. To investigatewhether deficiency of NF-L protein results in myelin alteration during ageing, thisthesis measured the relative protein level of myelin basic protein (MBP) by usingquantitative Western blot. It was demonstrated that the level of MBP wassignificantly reduced in the cortex of NF-L KO mice at 12 months, compared to WTmice.In summary, these findings indicate that pathological and compensatory neuronaleffects of NF-L KO and reduced NFs are affected by ageing. The absence of NF-Lprotein results in the alteration of NFs and other cytosekeletal, mRNA-binding and myelin proteins during ageing. These results indicate that the absence of NF proteinscan lead to abnormalities in neurodegenerative disease-related proteins, but also thatthe central nervous system (CNS) is capable of adaptive alterations in the absence ofNFs." @default.
• W183359539 created "2016-06-24" @default.
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• W183359539 date "2013-09-01" @default.
• W183359539 modified "2023-09-27" @default.
• W183359539 title "Role of neurofilaments in ageing andneurodegenerative disease" @default.
• W183359539 hasPublicationYear "2013" @default.
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