I received my BSc. (Hons) (Biomedical Sciences – Neuroscience, 2009) and PhD (Visual Neuroscience and Molecular Biology, 2012) from Cardiff University. I trained with Prof. James Morgan and Prof. Marcela Votruba studying dominant optic atrophy (DOA; an inherited childhood neuropathy driven by mutations in OPA1), in addition to Parkinson’s disease, Alzheimer’s disease, and glaucoma. Following a short collaborative period exploring retinal ganglion cell dendritic degeneration during early glaucoma pathogenesis I joined the laboratory of Prof. Simon John (The Jackson Laboratory) as a postdoctoral fellow in 2012 focusing on the early mechanisms that influence retinal and optic nerve degeneration in glaucoma. In 2017 I received a faculty funded career position at the Karolinska Institute where I formally started my lab in 2018.
My lab uses the eye as a model of the central nervous system to elucidate early mechanisms of neurodegeneration. We utilize modern transcriptomic and molecular tools to delicately dissect pathways pertaining to early aging and neurodegenerative disease mechanisms and to identify potential therapeutic targets which we then test and verify in animal and cell models of neurodegeneration. We work with clinicians to develop novel protective strategies that will benefit human health, aging, and disease.
Our current research explores early disease mechanisms in glaucoma, a leading neurodegeneration affecting ~80 million patients worldwide (an estimated 100,000 – 200,000 in Sweden alone). Using genomic/transcriptomic tools followed by cell molecular and neurobiological tests, we have recently discovered metabolic dysfunction and mitochondrial abnormalities occurring prior to neurodegeneration in a mouse model of inherited glaucoma (Williams et al., 2017, Science). Importantly, many of these changes are age-dependent and may sensitise retinal ganglion cells (the output neurons of the retina) leaving them vulnerable to the insults of elevated intraocular pressure (a major risk factor for glaucoma). One such molecule is the essential REDOX cofactor and metabolite NAD, which declines in the retina in an age-dependent manner. NAD is well established to be a potent mediator of axon (and thus neuronal) survival following damaging disease-related insults, and is thus an ideal target for neuroprotection in glaucoma. To this end, we have shown that supplementing NAD by administration of nicotinamide (the amide form of vitamin B3, an early precursor for NAD) or through gene therapy (Nmnat1, a terminal enzyme for NAD production in the soma) robustly protects from age-related neuronal metabolic decline and prevents glaucoma in a chronic mouse model of glaucoma. This is the first example of a successful gene therapy in a complex, polygenic disease.
My lab’s ongoing research furthers these findings by translating these discoveries to other glaucoma models, by testing other genes and molecules that influence NAD levels, and by testing the roles of mitochondrial health and homeostasis in glaucoma.
We collaborate with basic scientists and research clinicians to develop discoveries into targeted therapeutics in the clinic.
Retinal ganglion cell dendritic atrophy in DBA/2J glaucoma
PloS one 2013;8(8):e72282-
Retinal ganglion cell dendritic degeneration in a mouse model of Alzheimer's disease
Neurobiology of aging 2013;34(7):1799-806
Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity
Brain : a journal of neurology 2012;135(Pt 2):493-505
Mouse models of dominant optic atrophy: what do they tell us about the pathophysiology of visual loss?
Vision research 2011;51(2):229-34
Specific deficits in visual electrophysiology in a mouse model of dominant optic atrophy
Experimental eye research 2011;93(5):771-7
Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy
Brain : a journal of neurology 2010;133(10):2942-51