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Glial Cell Biology & CNS Repair Laboratory

MND, glial, oxidative stress...

Actin stress fibre formation (green) and rearrangement of the cytoskeleton protein GFAP (red) in astrocytes expressing an ALS-linked TDP-43 mutation

Research Summary

The central nervous system consists of two major cell populations: nerve cells and glial cells. Glial cells are subdivided into astrocytes, microglia and oligodendrocytes. Dysfunction and death of nerve cells and glia in the brain is a major determinant of the symptoms that develop in most neurological disorders. Studies in our laboratory are focused on the role of astrocytes in brain diseases, particularly in motor neuron disease. Astrocytes greatly outnumber neurons and play many roles essential for normal brain function. These cells make important contributions to activities including provision of precursors for amino acid neurotransmitters, buffering of ionic changes in the extracellular fluid and metabolite trafficking from the blood. Studies in recent years have revealed additional complexities in the interchange of metabolites and intercellular messengers between astrocytes and neurons, further demonstrating the important influences of astrocytes on neuronal function.

Astrocytes are also the major contributor to defence against oxidative damage and express glutamate transporters that clear excess glutamate from the synaptic cleft and the extracellular space. Loss of these transporters leads to excitotoxic damage. Thus, the extent of preservation of key astrocytic properties and the ability of these cells to mount appropriate defensive responses are likely to be important determinants of tissue viability in many neurological diseases.

Research Projects

This NHMRC funded project investigates the role of glial cells in the pathogenesis of motor neuron disease. The studies are undertaking in collaboration with Prof Phil Beart at Melbourne University. TDP-43 is a highly conserved 43-kDa DNA- and RNA binding protein, regulating transcription and splicing. This protein is abundantly expressed in neurons and glia. Abnormal processing and aggregation of TDP-43 are characteristic of, what are now known as, TDP-43 proteinopathies. Abnormal molecular weight TDP-43 fragments have been observed in both neurons and astrocytes in affected nervous tissues of patients from a spectrum of neurodegenerative diseases, including motor neuron disease and frontal lobe dementia. Over 18 mutations in the gene encoding for TDP-43 have been reported in motor neuron disease patients. A number of these mutations cause inherited forms of the disease. The mechanism by which mutant TDP-43 causes neurodegeneration is unknown and there is limited experimental evidence directly linking any individual mechanism to the complex picture of TDP-43-mediated pathology. In this study, we characterise the role of TDP-43 in normal cell function and investigate mechanisms behind TDP-43 pathology in astrocytes and motor neurons.

These studies are performed in collaboration with Prof Neil Sims under a joint NHMRC project grant. The studies aim to identify and modify the inflammatory response by glial cells after experimental induced stroke in rats.

In this study we aim to identify pharmacologically assessable target for treatment of motor neuron disease.

Selected Publications

Muyderman H, Chen T (2014) Mitochondrial dysfunction in amyotrophic lateral sclerosis - a valid pharmacological target? British Journal of Pharmacology, 171(8):2191-205

 

Peiris H, Dubach D, Jessup CF, Unterweger P, Raghupathi R, Muyderman H, Zanin MP, Mackenzie K, Pritchard MA, Keating DJ (2014) RCAN1 regulates mitochondrial function and increases susceptibility to oxidative stress in mammalian cells. Oxidative Medicine & Cellular Longevity, 2014:520316

 

Malmevik J, Rogers ML, Sims N, Rush RA, Nakanishi Y, Nilsson M, Muyderman H (2014) Selective transfection of microglia in the brain using an antibody-based non-viral vector. Brain Research, 1586:12-22

 

Muyderman H, Sims NR, Tanaka M, Fuku N, Raghupathi R, Thyagarajan D (2012) The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis. Mitochondrion, 12(4):465-71

 

Muyderman H, Yew WP, Homkajorn B and Sims NR (2010) Astrocytic responses to DNA delivery using Nucleofection. Neurochemical Research, 35(11):1771-1779

 

Homkajorn B, Sims NR and Muyderman H (2010) Connexin 43 regulates astrocytic migration and proliferation in response to injury. Neuroscience Letters, 486(3):197-201

 

Sims NR and Muyderman H (2010) Mitochondria, oxidative metabolism and cell death in stroke. Biochimica et Biophysica Acta, 1802(1):80-91

 

Rogers M-L, Bailey S, Matusica D, Nicholson I, Muyderman H, Pagadala PC, Neet KE, Zola H, Macardle P and Rush RA (2010) ProNGF mediates death of Natural Killer cells through activation of the p75NTR-Sortlin complex. Journal of NeuroImmunology, 226(1-2):93-103

 


Investigator

  • Håkan Muyderman, MD, PhD

Students

  • Wei Ping Yew, PhD Student (co-supervised with Neil Sims, Stroke Laboratory)


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