Although human Parkinson's disease is linked to dopamine loss, two distinct mutations in a kinase associated with familial Parkinson's operate downstream, altering excitatory synapses on dopamine-sensing neurons.
LRRK2 G2019S knock-in mice are a genetically faithful model that recapitulates the slow disease progression of familial PD, with initial alterations to behaviour and neurotransmission providing early pathophysiological targets for neuroprotective interventions.
The most common Parkinson’s disease-associated mutation, LRRK2 G2019S, impairs mitophagy in clinically relevant cells within the mouse brain and this defect can be reversed using a novel LRRK2 inhibitor.
Long studied in the context of the central nervous system, LRRK2 also functions in peripheral immunity by maintaining mitochondrial homeostasis in macrophages to regulate the type I interferon response.
Pathogenic LRRK2kinase requires Rab10 and RILPL1 to block primary cilia formation, shortening cilia on cholinergic neurons needed for a hedgehog driven circuit that supports dopaminergic neurons in mouse brain.
Vps29 promotes retromer localization in the adult Drosophila brain, engaging Rab7 and TBC1D5, and its loss triggers age-dependent neuronal impairments in endolysosomal trafficking and synaptic transmission.
The ASAP initiative promotes open and collaborative practices, and works with other foundations and projects in an effort to understand the mechanisms responsible for the onset and progression of Parkinson's.