Abstract:
Huntington’s disease (HD), a neurodegenerative disorder, is caused by a mutation in the IT15 gene that leads to the death of medium‐sized spiny neurons (MSSNs). The loss of MSSNs causes profound striatal atrophy, in a manner dependent on HD grade. To compensate for this cell loss, there is increased proliferation and neurogenesis in the subventricular zone (SVZ). Understanding what drives increased neuroproliferation and neurogenesis in the SVZ in HD is a current focus of neuroscience research as it could enable the enhancement of these endogenous neuroprotective mechanisms as a potential therapeutic intervention for neurodegenerative disease. The neuroproliferative effects of NPY have been previously demonstrated in cell culture studies and in animal models of HD. Further, there is evidence that these effects are elicited by activation of the Y1 receptor (NPY1‐R). As NPY interneurons are spared in the caudate nucleus (CN) in HD, the possibility that NPY may drive neuroproliferation and neurogenesis in the adult human SVZ was suggested. However, little research had been previously carried out in the adult human brain. This thesis is the first to look at NPY and NPY1‐R expression in the SVZ in normal and HD. The results indicated that these NPY+ cells are spared during HD, akin to NPY interneurons found in the CN. Western blots using CN homogenates normalised for mature neuron content, indicated an increase in NPY protein in HD. Thus, it is still possible that NPY may drive the neuroproliferation seen during HD, via the up‐regulation of NPY production by existing cells. Additionally, the proximity of NPY+ cells to cells expressing glial fibrillary acidic protein (GFAP), a marker of progenitor glial cells which undergo extensive proliferation, leading to the 2.8‐fold increase in thickness in the SVZ, lends evidence to the possible neuroproliferative role of NPY. The results also indicate the co‐expression of NPY, and nitric oxide synthase (NOS) and somatostatin (SMT). Since a role for NOS and SMT in regulating neuroproliferation has also been described, it is possible that these proteins may work in tandem with NPY to modulate its neuroproliferative role. Finally, a difference in NPY1‐R expression in the SVZ between normal and HD brains was also implicated. Thus, this thesis lends weight to the possible neuroproliferative role of NPY in the adult human SVZ.