Identification of protein targets of Smo signaling in cholinergic neurons that degenerate in Alzheimer’s Disease.

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This application seeks administrative supplement support for recently funded R21 AG065682-01 (award date 09/10/2020). The additional funding will allow the examination of Alzheimer’s Disease (AD) relevant brain nuclei in our otherwise Parkinson’s Disease (PD) focused analysis without expanding the scope, approach, or technology of the funded grant. Our funded research focuses on the role of Sonic Hedgehog (Shh), a cholinergic neuron trophic factor, in the cellular and neurochemical maintenance of the basal ganglia and its pathology in PD. We previously found that dopamine neurons of the mesencephalon (DAN) release Shh, which they use to communicate with cholinergic (CN) neurons in the striatum. Consistent with new imaging and preclinical findings that CN neurons degenerate in addition to DAN in PD, we found that the conditional ablation of Shh from DAN (ShhDAN-/-) results in adult onset neurodegeneration of CN. Our results suggests that boosting Shh effector activity in CN could promote CN survival and function in PD. The funded grant seeks to identify protein targets of ShhDAN signaling in CN of the striatum for the development of drugs that could protect CN from degeneration in PD. This work is enabled in our lab through in vivo metabolic labeling of mouse CN proteomes and the identification of ShhDAN dependent post-translational modifications via mass spectrometry. Our findings and approaches are also relevant to AD for three main reasons: (1) DAN also project outside of the basal ganglia to cholinergic neurons of the basal forebrain which degenerate in AD. (2) Recent imaging evidence reveals a significant loss of DANs in AD patients. Reduced levels of ShhDAN might therefore contribute to AD related CN degeneration. (3) Concordant, we found in preliminary results that ShhDAN-/- mice show a significant loss of CN in the basal forebrain. Together these findings suggest that effectors of ShhDAN signaling in CN of the basal forebrain could promote their survival. Here we seek funds that would allow us to include AD relevant tissues from the basal forebrain in our CN- specific proteomic analysis. The additional AD focused analysis would potentially identify targets of ShhDAN signaling unique to CN of the basal forebrain as well as targets relevant CN of both the striatum and basal forebrain. Thus, supplemental support would both deepen the interpretation of results obtained from the funded grant and in addition, potentially identify novel targets promoting CN survival in AD relevant brain nuclei.