Austen Milnerwood, PhD
础蝉蝉辞肠颈补迟别听笔谤辞蹿别蝉蝉辞谤
Austen Milnerwood鈥檚 research centers on cell biological, electrophysiological and optical investigation of neural development, connectivity, transmission and plasticity. With a major focus on the early pathophysiology of adult-onset diseases such as movement disorders and dementia, his laboratory aims to develop neuroprotective treatments. Our projects include behavioural studies in rodents, electrophysiology and cell biology in acute brain slices, primary neuronal co-cultures and patient stem cell-derived neuron models.
A strong theme has emerged from studying several proteins harbouring mutations聽that are autosomal dominantly linked to Parkinson鈥檚 disease, in other words, genes transmitted down the family line that are highly predictive for developing PD. There are several proteins that cause 鈥渇amilial PD,鈥� e.g. LRRK2, VPS35 and synuclein. Milnerwood's laboratory聽is聽finding that these proteins are involved in the same cellular functions. By learning more about what these proteins are supposed to do and what goes wrong with the mutations present, Milnerwood hopes to work out the common neuronal dysfunction of many forms of parkinsonism and then develop appropriate treatments.
Working out how neuronal function goes awry early in disease states can help聽to intervene and possibly to prevent the onset or progression of degenerative processes.聽The world鈥檚 population is aging. By 2025, half of the population may be over 60 years old, and up to 2% might have Alzheimer鈥檚 or Parkinson鈥檚 disease. There is a pressing societal and financial need to learn more about, and to better treat, human neurodegenerative disease.
Neurodegenerative Disorders
Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP,聽Milnerwood聽AJ, Unni VK, Hirst WD, Yue Z, Zhao HT, Fraser K, Kennedy RE, West AB.(2016)聽G2019S-LRRK2 Expression Augments 伪-Synuclein Sequestration into Inclusions in Neurons.聽J Neurosci.聽
Volta M., Cataldi, S., Beccano-Kelly D.A., Munsie L.N., Tatarnikov I., Chou P., Bergeron S., Mitchell E., Lim R., Khinda, J.,聽Lloret A., Bennett C.F., Paradiso C., Morari M., Farrer M.J. &聽Milnerwood聽A.J. (2015)聽Chronic and acute LRRK2 silencing has no long-term behavioral effects, whereas wild-type and mutant LRRK2 overexpression induce motor and cognitive deficits and altered regulation of dopamine release.聽Parkin. & Rel. dis.聽
Volta M,聽Milnerwood聽AJ, Farrer MJ. (2015)聽Insights from late-onset familial parkinsonism on the pathogenesis of idiopathic Parkinson's disease.聽Lancet Neurol.聽
Beccano-Kelly D.A., Volta M., Munsie L.N., Paschall S. A., Tatarnikov I., Co K., Chou P., Cao L.P., Bergeron S., Mitchell E., Han H., Melrose H.L., Tapia L., Raymond L.A., Farrer M.J. &聽Milnerwood聽A.J. (2015)聽LRRK2 overexpression alters presynaptic glutamatergic plasticity, striatal dopamine tone, postsynaptic signal transduction, behavioral activity and long-term memory.聽Hum Mol Gen.
Munsie L.N.,聽Milnerwood聽A.J.,聽Seibler, P.聽Beccano-Kelly D.A.,聽Tatarnikov I.T.,聽Kindah, J.,聽Volta M.,聽Kadgien C., Cao L.P., Tapia L. Klein C.聽& Farrer M.J. (2015)聽Retromer-dependent neurotransmitter receptor trafficking to synapses is altered by the Parkinson鈥檚 Disease VPS35 mutation p.D620N.聽Hum Mol Gen.聽
Beccano-Kelly D.A., Kuhlmann, N., Tatarnikov I., Volta M., Munsie L.N., Chou P., Cao L.P., Han H., Tapia L.,Farrer M.J. &聽Milnerwood聽A.J.聽(2014)聽Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice.聽Front. Cell. Neurosci.聽
Brigidi G.S., Sun Y.,聽Beccano-Kelly D.A., Pitman K., Borgland S.L.,聽Milnerwood聽A.J.聽& Bamji S.X. Delta-catenin Palmitoylation is Essential for Activity-dependent Enhancements of Synapse Structure and Efficacy聽(2014).聽Nat Neurosci.聽
Milnerwood聽A. J., Parsons M., Young F., Singaraja, R.,聽Volta M.,聽Bergeron S., Hayden, M.R. & Raymond, L. A. (2013) Cognitive deficits and severe disruption of synaptic transmission and plasticity in HIP14 palmitoyl transferase knock-out mice.聽PNAS聽
Milnerwood聽A.J., *Kaufman A.M., Sepers M., Gladding C.M., Fan, J., Coquinco, A., Zhang L.Y., Wang L., Qoi J., Lee H., Cynader, M. & Raymond L.A. (2012) Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington鈥檚 disease mice.Neurobiol Dis.聽
Kaufman A.M., *Milnerwood聽A.J., Sepers M., Coquinco A., She K., Wang L., Lee H., Craig A.M., Cynader M. & Raymond L.A. (2012) Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in striatal and cortical neurons.聽J. Neurosci.聽
Petkau T., Neal S.J.,聽Milnerwood聽A. J., Mew A., Hill A.M., Orban P., Gregg J., Lu H., Feldman H.H., Mackenzie I.R.A., Raymond L.A. & Leavitt B.R. (2012). Synaptic dysfunction in progranulin-deficient mice.聽Neurobiol.Dis.
Tapia L.,聽Milnerwood聽A. J., Guo A., Mills F., Yoshida E., Vasuta O.C, Mackenzie I., Raymond, L. A., Cynader M., Jia W., Bamji S.X. (2011).聽PGRN Deficiency Decreases Neural Connectivity But Enhances Synaptic Transmission at Individual Synapses.聽J. Neurosci.聽
Raymond LA, Andr茅 VM, Cepeda C, Gladding CM,聽Milnerwood聽AJ, Levine MS. (2011)聽Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.聽Neuroscience.聽
Milnerwood聽A. J.聽, Gladding C. M., Pouladi M. A., Kaufman A.M., Hines R. M., Boyd聽 J., Ko R.W.Y., Vasuta O. C., Graham R. K., Hayden M. R., Murphy T. H. & Raymond L. A. (2010). Early increase in extrasynaptic NMDA receptor signalling and expression contributes to phenotype onset in Huntington's disease mice.聽Neuron
Milnerwood聽A. J.聽& Raymond L. A. (2010). Early Synaptic Pathophysiology in Neurodegeneration: Insights from Huntington鈥檚 disease.聽Trends in Neurosciences聽
Milnerwood聽A. J.聽& Raymond, L. A. (2007). Corticostriatal Synaptic Function in Mouse Models of Huntington's Disease: Early Effects of Huntingtin Repeat Length and Protein Load.聽J. Physiol.聽
Cummings D. M.,聽Milnerwood聽A. J., Dall茅rac G.M., Vatsavayai S. C., Hirst M. C. & Murphy, K. P. (2007). Abnormal cortical synaptic plasticity in mice transgenic for human Huntington's disease mutation.聽Brain. Res. Bull.
Milnerwood聽A. J., Cummings D. M., Dall茅rac G.M., Brown J. Y., Vatsavayai S. C., Hirst M. C., Rezaie P. & Murphy, K. P. (2006). Early development of aberrant synaptic plasticity in a mouse model of Huntington鈥檚 disease.聽Hum. Mol. Gen.