lrrk2

LRRK2 – a master regulator of neurodegeneration: acting on multiple systems including neuroinflammatory signaling, vesicular trafficking, and cell death pathways

The synaptic functions of Alpha Synuclein and Lrrk2

Alpha synuclein and Lrrk2 are key players in Parkinson's disease and related disorders, but their normal role has been confusing and controversial. Data from acute gene-editing based knockdown, followed by functional assays, will be presented.

Synaptic health in Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. Dopaminergic neuronal loss is hallmark in PD and yet despite decades of intensive research there is still no known therapeutic which will completely halt the disorder. As a result, identification of interventive therapies to reverse or prevent PD are essential. Using genetically faithful models (induced pluripotent stem cells and knock-in mice) of familial late onset PD (LRRK2 G2019S and GBA N370S) we have contributed to the literature that neuronal dysfunction precedes degeneration. Specifically, using whole cell patch clamp electrophysiology, biochemical, behavioural and molecular biological techniques, we have begun to investigate the fundamental processes that make neurons specialised i.e., synaptic function and neurotransmission. We illustrate those alterations to spontaneous neurotransmitter release, neuronal firing, and short-term plasticity as well as Ca2+ and energy dyshomeostasis, are some of the earliest observable pathological dysfunctions and are likely precursors to late-stage degeneration. These pathologies represent targets which can be manipulated to address causation, rather than the symptoms of the PD, and represent a marker that, if measurable in patients, could form the basis of early PD detection and intervention.

Characterization of the autophagic-lysosomal pathway in Parkinson’s disease using patient iPSC-derived dopaminergic neurons containing a LRRK2 G2019S mutation

FENS Forum 2024

Characterizing LRRK2 in varying states of phosphorylation

LRRK2-G2019S mutation at the interface of astrocyte-neuron cross-talk during early post-natal development

Parkinson’s disease LRRK2-G2019S disrupts HDAC6-mediated recruitment of misfolded protein aggregates into aggresomes

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease