We hypothesize that vulnerable neurons (SN/LC) have intrinsic properties within axonal and/or somatodendritic compartments that render them vulnerable to PD stressors (e.g. activity pattern, ion channel function, bioenergetic demands, intrinsic metabolic stress, transmitter release mechanisms, complex Ca2+ signalling), whereas resistant / less vulnerable neurons (VTA/DMV) exhibit less demanding intrinsic activities, or activate defence mechanisms that enable survival.

We focus:

• on the contribution of voltage gated Ca²⁺ channels, since an inhibitor is currently in a phase III clinical trial for PD, yet pathogenesis mechanisms are unclear.

• on mitochondrial and lysosomal function that are emerging as central to neuronal Ca²⁺ signalling and metabolic stress.

• on SN DA neurons, crucial for PD motor symptoms.

Our multidisciplinary CalPark consortium combines unique experimental approaches from fundamental, pre-clinical and clinical PD research crossing discipline boundaries and technologies, and forming an unrivalled team who will deliver novel defined targets and strategies for therapy in PD, with the potential also to identify novel therapeutic avenues for a wider spectrum of neurodegenerative diseases with related turning points and pathogenesis.