Parkinson’s progress: novel genes, mouse models and synthesis
Parkinson’s disease (PD) is a multifaceted, age-associated syndrome best known for movement disorder but also affects autonomic, cognitive, psychiatric, sensory and sleep systems. Progressive loss of dopaminergic neurons disrupts cortical and thalamic neurotransmission, and the ability to modulate striatal outputs necessary to initiate and control motor function. Mechanisms of neuroplasticity and compensation in PD brain are poorly understood but evidently mask symptoms until they fail. While mid-brain Lewy body pathology is typically noted at post-mortem, its relationship with respect to clinical symptoms remains enigmatic. Over the past 20 years my group has taken a molecular genetic view to define the etiology of PD. We have used mutant gene dysfunction to recapitulate disease ontology, and have focused on mouse modelling. Notable discoveries include alpha-synuclein (SNCA) dosage is correlated with onset and severity, and that leucine-rich repeat kinase 2 (LRRK2) p.G2019S is a major cause of disease, frequent in Berbers. My seminar will present our latest gene discovery, loss of DNAJC12, and data from mouse modelling of vacuolar protein sorting 35 (VPS35) p.D620N. From these observations I suggest mutant-induced dysfunction challenges presynaptic proteostasis, inducing activity-dependent modifications in the synaptic vesicle cycle and dopaminergic neurotransmission. Several genes ‘linked’ to parkinsonism, including SNCA, LRRK2, VPS35DNAJC12, DNAJC13, DNAJC6, DNAJC26, SYNJ1, parkin and PINK1 have a presynaptic role and may be unified by this hypothesis. While the failure of adaptive changes, with age, leads to the selective and progressive loss of dopaminergic neurons, there are now tools to define these molecular pathways and their potential for neuroprotection.
Date: 6 October 2017, 13:00 (Friday, 0th week, Michaelmas 2017)
Venue: Sherrington Building, off Parks Road OX1 3PT
Venue Details: Large Lecture Theatre
Speaker: Professor Matt Farrer (University of British Columbia)
Organising department: Department of Physiology, Anatomy and Genetics (DPAG)
Organiser: Professor Richard Wade-Martins (Professor of Molecular Neuroscience, University of Oxford)
Organiser contact email address:
Host: Professor Richard Wade-Martins (Professor of Molecular Neuroscience, University of Oxford)
Part of: OPDC Seminar Series (DPAG)
Booking required?: Not required
Audience: Members of the University only
Editor: Sally Collins