Julie Atkin
BSc(Hons)(Manchester) PhD (Sheffield) Grad Dip
Brain Injury and Repair Group
Neurodegeneration Laboratory
Contact Details
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Phone: | +61 (0)3 8344 9697 |
Fax: | +61 (0)3 9348 1707 |
Research Interests
Motor Neuron Disease (MND) is a rapidly progressive and fatal neurodegenerative disorder. Abnormal aggregation of the protein superoxide dismutase (SOD1) appears to be a central feature of both the sporadic and familial forms and results in abnormal protein inclusions in motor neurons. Protein aggregation is likely to be central in pathogenesis but whether inclusions are cytotoxic or cytoprotective is debated. Resolving this question and identification the events that initiate aggregation and inclusion formation will be important for understanding the cause of MND.
Our research is focused on the role of cellular trafficking and endoplasmic reticulum (ER) stress in the pathology of MND. In recently published findings we showed that ER stress and the unfolded protein response (UPR) are central to neuronal death in MND. Misfolding and aggregation of proteins in the ER occurs normally, but when it persists, the UPR signalling pathway is triggered. Although initially protective, prolonged UPR triggers specific apoptotic signals; CHOP and caspase 4/12. The UPR was induced in (a) lumbar spinal cords of SOD1G93A mice (Atkin et al 2006; the most widely accepted animal model of MND) and more importantly, in (b) lumbar spinal cords of human patients with the predominant sporadic disease (Atkin et al 2008), thus placing ER stress centrally in the pathophysiology of all MND.
It is puzzling that motor neurons are selectively targeted in MND when SOD1 is ubiquitously expressed. One possible explanation is that motor neurons have long axons, and axonal transport disturbances are well documented in MND patients and animal models. The dynein transport machinery drives cellular transport, and it also plays an essential role in aggresome formation. Mice with mutations in dynein develop motor neuron degeneration and mutant SOD1 binds to dynein.
Protein disulphide isomerase
Protein disulphide isomerase (PDI) is an ER chaperone induced during ER stress. PDI is the prototype of a family of 19 chaperones that are induced during the UPR and which contain the same active site. The PDI family possesses general chaperone activity but it is also the main group of enzymes responsible for the formation and isomerisation of protein disulphide bonds. We were the first laboratory to demonstrate that PDI is upregulated in MND and that the UPR is induced in human MND as well as in animal models of disease (Atkin et al 2006; 2008). PDI was also detected in the cerebrospinal fluid (CSF) of MND patients and animal disease models.
We are also examining whether the UPR and PDI are possible therapeutic targets for MND. Pharmacological agents that modulate PDI and ER stress are currently being administered to SOD1G93A mice and their affect on disease onset and progression will be examined. The pathogenesis of MND remains elusive and this prevents the design of effective therapeutic strategies. Targeting PDI and the UPR in therapeutic intervention (as suggested by our published and unpublished data) is a novel concept in MND.
The lack of effective therapies coupled with the aging population and the incipient projected dramatic increase in the number of persons with neurodegenerative disorders in the coming decades, highlights the need to urgently find effective treatment strategies for these conditions.
Research Grants Awarded
- 2007-2010 NH&MRC Project Grant $519,000
"Is there a role for endoplasmic reticulum stress in ALS?”
New Investigator Project Grant - 2004-2007 MND Research Institute of Australia Fellowship $120,000
"Human ALS linked to SOD1 mutations: Mechanisms of toxicity in motor neurons." - 2005-2006 ALSA (The ALS Association, USA), US$40,000,
“A neuroprotective role for Protein Disulphide Isomerase in ALS?” - 2006 ANZ Medical Research Technology of Australia $8,000
- 2007 Australian Brain Foundation $40,000
"A new hypothesis of Motoneuron Disease: astrocytes are the non-neuronal neighbours inducing motoneuron injury" - 2008 Bethlehem Griffiths Research Foundation $45,000
“Is endoplasmic reticulum stress primarily responsible for cell death in MND?”. - 2008 MND Research Institute of Australia - The Henry H Roth Charitable Foundation Grant for MND Research $25,000
“Is ER stress primarily responsible for cell death in MND?” - 2009 MND Research Institute of Australia $25,000
“New therapeutic approaches for MND based on ER stress inhibition”
Recent Publications and Articles (2004-)
Turner B J, Laughton K M, Masters C L, Atkin J D, Cheema SS
“Brain ß-Amyloid Accumulation In Transgenic Mice Expressing Mutant Superoxide Dismutase 1”
Neurochem Res., Vol 29, No 12, 29(12):2281-6 2004
Turner BJ, Atkin J D, Farg MA, Zang DW, Rembach A, Lopes EC, Patch J D, Hill AF, Cheema SS
“Impaired Extracellular Secretion Of Mutant SOD1 Associates With Neurotoxicity In Familial Amyotrophic Lateral Sclerosis”
J. Neuroscience Vol 25(2): 108-117 (2005)
Atkin J D, Scott R L, Quah A, West JM, Lopes E, Cheema SS
“Properties Of Fast- And Slow- Twitch Muscles In A Mouse Model Of Amyotrophic Lateral Sclerosis”
Neuromusc. Dis. 15: 377-388 (2005)
Lewis MJ, Pleass R, Batten M R, Atkin J D, Woof JM
“Structural Requirements For The Interaction Of Human Immunoglobulin A With The Human Polymeric Immunoglobulin Receptor”
J Immunol 175: 6694-6701 (2005)
Atkin J D
“Mysteries Of The Motor Neuron”
Australiasian Science, August 2005; 22-24
(Invited review) Turner B J and Atkin J D
“ER Stress and UPR in Familial Amyotrophic Lateral Sclerosis”
Curr Mol Med 6, 79-86 (2006)
Atkin J D, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK
“Induction Of The Unfolded Protein Response In Familial ALS And Association Of Protein Disulfide Isomerase With SOD1”
J Biol Chem 281 (40): 30152-65 (2006)
Juan L, Zang D, Atkin J D
“Increased Number And Differentiation Of Neural Precursor Cells In The Brainstem Of Superoxide Dismutase 1(G93a) (G1h) Transgenic Mouse Model Of Amyotrophic Lateral Sclerosis”
Neurol Res. Mar;29(2):204-9 2007 (IF=1.6).
Atkin J D, Farg MA, Walker AW, Mcclean C, Tomas D,Horne MK
“Induction Of The Unfolded Protein Response In Human Sporadic ALS”
Neurobiol Of Disease 30: 400-407 (2008) (IF=4.2)
Turner BJ and Atkin J D (Invited Book Chapter).
“Coupling ER Stress To Motor Neuron Degeneration In ALS”
In: Columbus F. (Ed.) Motor Neuron Disease Research Progress, Nova Sciences Publishers, New York. (2008)
Stam N C, Nithianantharajah J, Howard M L, Atkin J D, Cheema SS, Hannan AJ
“Sex-Specific Behavioural Effects Of Environmental Enrichment In A Transgenic Mouse Model Of Amyotrophic Lateral Sclerosis”
Eur J Neurosci 28: 717-723 (2008). (IF=4.1)
T M. Woodruff, Costantini K J, Crane J W, Atkin J D, Monk P N, S M. Taylor, and P G. Noakes “The Complement Factor C5a Contributes To Pathology In A Rat Model Of Amyotrophic Lateral Sclerosis”
J Immunol 181(12): 8727-34 (2008) (IF= 6.1)
Soo K Y, Atkin J D, Horne M K, Nagley P
“Mutant SOD1 Expression Results in the Recruitment Of Mitochondria Into Apoptotic Signalling Due To Cytotoxic Inclusion Formation”
J Neurochem 108: 578-590 (2009) (IF=4.5)
(Invited review) Walker AK, Turner B J, Atkin J D
“Endoplasmic Reticulum Stress And Protein Misfolding In Amyotrophic Lateral Sclerosis”
E Pub In "Stress Responses And Protein Misfolding Disorders" Bentham Science Publishers (2009; in press).
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