AbstractFUS is a DNA/RNA-binding protein that modulates gene expression by associating with a wide range of transcription-related factors in the nucleus and/or cytoplasm of neurons. Abnormal expression or mutation of FUS were reported to be involved in the pathologies of ALS and FTLD. Since both pathologies include neurodegeneration, the synapse weakening process might be exhibited prior to the neuronal death. However, there are missing gaps not well explained.
In this PhD study, the nature and consequence of abnormal FUS were investigated in terms of the potential pathology, involved in ALS, FTLD and other possible neurodegenerative diseases. By utilising main pathogenic factors of FUS (NLS mutation and hypomethylation), both morphological and neurophysiological alterations by abnormal expression and propagation of FUS were investigated.
First, cytosolic accumulation of FUS was investigated using FUS-P525L, which has mutation on NLS region, required for nuclear internalisation of FUS. FUS-P525L was shown to have quicker translocation though the dendrites than that of FUS-WT and this difference resulted in the reduction of spine density in the apical dendrites of FUS-P525L cells. FUS-P525L cells were shown to have increased synaptic conductance and intrinsic excitability and the excitability was returned to the control level when Calcium-permeable AMPAR blocker IEM-1460 was applied. And had decreased basal synaptic transmission and inhibited induction of LTP and LTD.
Second, FUS mutant with enhanced cation-π interaction was investigated by using FUS-16R, which has 16 additional arginine residues, increases the chance of hypomethylation. The spine density of FUS-16R cells were shown to be reduced in both basal and apical dendrites compared to FUS-WT cells. In addition, intrinsic excitability and basal synaptic transmissions were reduced in FUS-16R cells.
Together, the results suggest that abnormal expression of FUS mutant is widely involved in the morphological, electrophysiological synapse weakening and it is related to the neuronal activity and excitability.
|Date of Award||11 May 2021|
|Supervisor||Daniel Whitcomb (Supervisor) & Shelley Allen-Birt (Supervisor)|