Austen J Milnerwood

Assistant Professor in Neurology,
Department of Medicine, UBC
Centre for Applied Neurogenetics
Brain Research Centre

Phone: 604 827 1085

Web pages: Centre for Applied Neurogenetics



  • PhD Open University (UK) 2005
    Department of Biological & Life Sciences
  • BSc (Hons.) First Class University of Hertfordshire (UK) 2000
    Department of Biology


  • Neurophysiology
  • Neurodegeneration
  • Learning and Memory
  • Pathophysiology of late onset disease
  • Huntington's Disease
  • Parkinson's Disease and related disorders
  • Dementia

Research Interests

Dr Milnerwood has >13 years’ experience of neurobiological and electrophysiological investigation of neuronal connectivity, transmission and plasticity in rodents, acute brain slices and primary neuronal co-culture models. “To my mind, there is little that can be more exciting to investigate than the inner workings of the squishy brain that produces it. Brains and neurones exist to perform a function, and it is unlikely in neurodegenerative diseases that brain cells function perfectly until the moment they expire. Working out how neuronal function goes awry in disease states – determining the pathophysiology – can help us intervene and prevent the onset and/or progression of degenerative processes. In our progressively long-lived global population, disorders of the nervous system are becoming increasingly prevalent. Given that estimates suggest >50% of the global population will be over 60 years of age by 2025, and that 2% of us will have Alzheimer’s or Parkinson’s disease, there is a pressing societal and financial need to learn more about, and to better treat, human neurodegenerative diseases”.

A major focus for our programs are proteins that are autosomal dominantly linked to Parksonson’s disease i.e., transmitted down the family line and highly predictive of developing PD. Several proteins are major contributors to familial PD; LRRK2, VPS35, DNAJC13/RME8 and synuclein, and we are finding that they 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, we hope to work out the common neuronal dysfunction to many forms of parkinsonism and develop appropriate treatments.

Current Programs of Research

Neurobiology of Retromer and VPS35 PD mutations

CAN recently discovered a PD-causal mutation (p.D620N), within VPS35; a protein largely uncharacterised in neurones. We have a large program centred on determining the basic neurobiology of VPS35, it’s role in the retromer complex, and the effects of the DN mutation. Lines of investigation include retromer cargo binding and trafficking, endosomal sorting, neuronal transmission and receptor recycling in cell lines, mature (>3 weeks in vitro) neuronal culture systems, drosophila models and transgenic knock-in mice.
Current support: CIHR Operating Grant Molecular Neuroscience of Parkinson’s Disease: Retromer (VPS35) Dysfunction. Co-Investigators Matthew Farrer, Austen Milnerwood.

The role of LRRK2 in Neurotransmission

Very little is known about the neuronal function of this important protein. Our experiments probe the effects of deletion and overexpression of this protein in cultured neurones and transgenic mice, to help us understand what LRRK2 does, in order to understand what goes wrong in LRRK2-Parkinsons Disease. Electrophysiological investigation of synaptic transmission and confocal microscopy of cellular and synaptic markers are key to this project.
Current Support: Michael J Fox Foundation “The role of LRRK2 in Neurotransmission”. Principle Investigator Austen Milnerwood

Early pathophysiology and intervention strategies in LRRK2 transgenic models of PD

We are using a sophisticated combination of knock-in and transgenic mice, optogenetic neuronal stimulation, voltammetry, electrophysiology, behavior and microdialysis to probe the earliest negative effects of LRRK2 mutations in the brain. By working out what goes wrong first, we expect to design drug treatments that can prevent the onset and progression of LRRK2 and sporadic PD.

Synuclein, LRRK2 and Tau interactions

What we know about the brain of LRRK2 PD patients suggests that the same symptoms are produced by different pathologies, even though the underlying mutations are the same. We are studying Tau and synuclein pathology in LRRK2 mice to see how the overexpression, deletion and mutation of LRRK2 change acutely induced Tau and synuclein disease states, in collaboration with Virginia Lee (U Penn). By working out the commonalities between these models we expect to gain insights about the mechanisms that are fundamental to all PD.
Current Support: CERC Principle Investigator Matthew J Farrer, Investigator Austen Milnerwood

Hyperplasticity in novel neuronal co-culture systems

Morphological plasticity is extensively studied as a physical correlate of activity-dependent changes in neural connectivity and information storage. Most of the literature has focused on excitatory synapses of the hippocampus and cortex and activity-dependent changes in dendritic spine size/shape. We use a co-culture system in which GABAergic striatal medium-spiny neurones (MSNs) are grown with glutamatergic cortical cells. In the absence of glutamate transmission MSNs do not develop spines, but rapidly form them when glutamate signaling is pharmacologically unveiled. This postsynaptic structure is highly dynamic in MSNs and is readily manipulated for the study of molecular and synaptic determinants of neuronal morphological plasticity.

Synaptic physiology of Huntington’s disease KI mice

Early alterations in synaptic function are observed in many mouse models of HD, and we have found changes prior to obvious motor phenotypes in subtle knock-in mice. In collaboration with Vanessa Wheeler (Harvard) we are probing the genetic and molecular basis for these synaptic disturbances.

Excitatory synaptic transmission and maintenance in developing neurones

In collaboration with UBC’s Bamji Lab, we study scaffolding molecules e.g., catenin, that regulate synaptic connectivity and maintenance in hippocampal neurones. These structural proteins enable synapses to form and change through dynamic activity-dependent regulation of post-translational modifications such as palmitoylation. 

For more about Dr. Milnerwood's research interests and research techniques please visit The Centre for Applied Neurogenetics - Translational Neuroscience.

Selected Publications

*Milnerwood 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. Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington's disease mice. Neurobiol Dis. 2012 Jun 2;48(1):40-51.

Gladding C.M., Sepers M., Xu, J., Zhang L.Y., Milnerwood A.J., Lambroso P. & Raymond L.A. Calpain and Striatal Enriched Protein Tyrosine Phosphatase (STEP) Activation Contribute to Extrasynaptic NMDA Receptor Localization in a Huntington's Disease Mouse Model. Hum Mol Genet. 2012 Jun 23.

*Kaufman A.M., *Milnerwood 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. J. Neurosci. 32(12):3992-4003.

Fan J., Gladding C.M., Wang L., Zhang L., Kaufman A.M., Milnerwood A.J. & Raymond L.A. (2012). P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol Dis. 45(3):999-1009.

Petkau T.L., Neal S.J., Milnerwood 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. Neurobiol Dis. 45(2):711-22.

Raymond, L.A., Andre V.M., Cepeda C., Gladding C.M., Milnerwood A.J., Levine M. (2011) Pathophysiology of Huntington's Disease: Time-Dependent Alterations in Synaptic and Receptor Function. Neuroscience. 198:252-73.

Chartier-Harlin M-C., Dachsel J.C, Vilariño-Güell C., Lincoln S.J., Leprêtre F., Hulihan M.M., Kachergus J., Milnerwood A.J., Tapia L., Song M.S., Le Rhun E., Mutez E., Larvor L., Duflot A., Vanbesien-Mailliot C., Kreisler A., Ross O.A., Nishioka K., Soto-Ortolaza A.I., Cobb S.A., Melrose H.A., Behrouz B., Keeling B.H., Bacon J.A., Hentati E., Williams L., Yanagiya A., Sonenberg N., Lockhart P.J., Zubair A.C., Uitti R.J., Aasly J.O., Krygowska-Wajs A., Opala G., Wszolek Z.K., Frigerio R., Maraganore D.M., Gosal D., Lynch T., Hutchinson M., Bentivoglio A.R., Valente E.M., Nichols W.C., Pankratz N., Foroud T., Gibson R.A., Hentati F., Dickson W.D., Destée A. & Farrer M.J.(2011) Translation initiator EIF4G1 mutations in familial Parkinson's disease. Am J. Hum Gen. 89:398- 406.

Tapia L., Milnerwood A. J., Guo A., Mills F., Yoshida E., Vasuta O.C, Mackenzie I., Raymond, L. A., Cynader M., Jia W., Bamji S.X. (2011). PGRN Deficiency Decreases Neural Connectivity But Enhances Synaptic Transmission at Individual Synapses. J. Neurosci. 31(31):11126-32.

Singaraja R.R., Huang K., Sanders S.S., Milnerwood A.J., Hines R., Lerch J.P., Franciosi S., Drisdel R.C., Vaid K., Young F.B., Doty C., Wan J., Bissada N., Henkelman R.M., Green W.N., Davis N.G., Raymond L.A., Hayden M.R. (2011) Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum. Mol. Gen. 20(20):3899-909.

Dallérac G.M., Vatsavayai S. C., Cummings D. M., Milnerwood A. J., Hirst M. C. & Murphy, K. P. (2011). Impaired Synaptic Plasticity in the Prefrontal Cortex of Huntington's Disease Mouse Models is Reversed by Dopamine Receptor Activation. Neurodegener Dis. 8(4):230-9. PMID: 21282937.

You can find a full list of Dr. Milnerwood's publications here.


Dr Milnerwood is always looking to recruit talented and enthusiastic individuals at all levels, please contact for details regarding current opportunities