Investigating the relationship between amyloid and synuclein in their effects on synapses and in Alzheimer's and Parkinson's disease.

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Many observations suggest there is some connection between Parkinson's disease (PD) and Alzheimer's disease (AD) and between synuclein (syn) and amyloid (A). PD and AD have shared neuropathologies and may thus share common pathological mechanisms. Senile plaques, which characterise AD, are frequently present in Parkinson's and other synucleinopathies. Conversely, Lewy bodies, composed of syn aggregates which characterise PD are present in a majority of both familial and sporadic forms of AD. Recently it has been found that levels of syn and A in blood and CSF are, respectively, useful biomarkers for AD and synucleinopathies. PD and AD are both now regarded as synatopathies and both at later stages feature tau pathology. Indeed, the synaptic effects of A and those of syn have both been found to be tau-dependent. A fragment of syn (termed the non-amyloid component) is present in senile plaques. It is well established that the synuclein protein and A peptides directly interact with each other. It is claimed that -syn is, if not an active, is at least a passive, player in the pathophysiology of AD. Finally, oligomeric forms of A enhance the synaptotoxic effects of syn and A deposits promote the seeding and spread of syn. We, and several other groups, have shown that aberrant Wnt signalling is key to synapse loss and other aspects of Alzheimer's neuropathology. Growing evidence indicates a dysregulation of Wnt also plays a role in Parkinson's and other synuleinopathies. In support of this Wnt signaling is a key player in dopaminergic neuronal differentiation and survival and has been suggested as an avenue for therapeutic intervention for PD. The PD gene LRRK2 has been shown to interact with components of the canonical and non-canonical branches of Wnt pathways and to modulate the activity of both, within the synapse. A second PD gene, VPS35, has also been shown to modulate Wnt activity. Both LRRK2 and VPS35 directly interact with the Wnt receptor component, LRP6, which we have shown interacts with the amyloid precursor protein (APP) and is a crucial player in Wnt-ROCK-mediated, A-driven synapse loss and a modulator of neuronal A production. In further support of the Wnt-ROCK pathway in particular, ROCK expression is altered in dopaminergic neurons in affected brain regions in mouse models of PD and ROCK inhibition protects dopaminergic neurons. The major aim of this project is to uncover the biochemical nature of the relationship between synuclein and amyloid. That is, more specifically we aim to determine how the two proteins act in the cell signalling pathway through which they each impact synapse function and morphology. It is the working hypothesis of the project that Wnt signalling is key pathway involved in these processes and the key aim is to determine where and what role synuclein plays in this pathway, which the group have already established is activated and driven by amyloid.