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About me

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.

Research description

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.

Documents

Publications

Nicotinamide treatment robustly protects from inherited mouse glaucoma
Williams Pa, Harder Jm, Cardozo Bh, Foxworth Ne, John Swm
Communicative & integrative biology 2018;11(1):e1356956-

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective
Harder Jm, Braine Ce, Williams Pa, Zhu X, Macnicoll Kh, Sousa Gl, et al
Proceedings of the National Academy of Sciences of the United States of America 2017;114(19):E3839-E3848

Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma
Williams Pa, Harder Jm, John Swm
Journal of glaucoma 2017;26(12):1161-1168

GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma
Williams Pa, Braine Ce, Foxworth Ne, Cochran Ke, John Swm
Journal of neuroinflammation 2017;14(1):93-

Neuroinflammation in glaucoma: A new opportunity
Williams Pa, Marsh-armstrong N, Howell Gr, Lasker/irrf Initiative On Astrocytes And Glaucomatous Neurodegeneration Participants
Experimental eye research 2017;157():20-27

Nicotinamide and WLDS Act Together to Prevent Neurodegeneration in Glaucoma
Williams Pa, Harder Jm, Foxworth Ne, Cardozo Bh, Cochran Ke, John Swm
Frontiers in neuroscience 2017;11():232-

Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice
Williams Pa, Harder Jm, Foxworth Ne, Cochran Ke, Philip Vm, Porciatti V, et al
Science (New York, N.Y.) 2017;355(6326):756-760

Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma
Williams Pa, Tribble Jr, Pepper Kw, Cross Sd, Morgan Bp, Morgan Je, et al
Molecular neurodegeneration 2016;11():26-

A Miniature, Fiber-Coupled, Wireless, Deep-Brain Optogenetic Stimulator
Lee St, Williams Pa, Braine Ce, Lin Dt, John Sw, Irazoqui Pp
IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society 2015;23(4):655-64

Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities
Fernandes Ka, Harder Jm, Williams Pa, Rausch Rl, Kiernan Ae, Nair Ks, et al
Experimental eye research 2015;141():42-56

Retinal ganglion cell dendritic atrophy in DBA/2J glaucoma
Williams Pa, Howell Gr, Barbay Jm, Braine Ce, Sousa Gl, John Sw, et al
PloS one 2013;8(8):e72282-

Retinal ganglion cell dendritic degeneration in a mouse model of Alzheimer's disease
Williams Pa, Thirgood Ra, Oliphant H, Frizzati A, Littlewood E, Votruba M, et al
Neurobiology of aging 2013;34(7):1799-806

Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity
Williams Pa, Piechota M, Von Ruhland C, Taylor E, Morgan Je, Votruba M
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?
Williams Pa, Morgan Je, Votruba M
Vision research 2011;51(2):229-34

Specific deficits in visual electrophysiology in a mouse model of dominant optic atrophy
Barnard Ar, Charbel Issa P, Perganta G, Williams Pa, Davies Vj, Sekaran S, et al
Experimental eye research 2011;93(5):771-7

Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy
Williams Pa, Morgan Je, Votruba M
Brain : a journal of neurology 2010;133(10):2942-51

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