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Shane Ravenhill Graduate Researcher, Psychology

Title: The temporal impacts and biological triggers of neuroinflammation on neurodegenerative disease progression, onset and severity in Parkinson’s Disease.

Defining the problem: Parkinson’s disease (PD), is a chronic and progressive age-related neurodegenerative illness, affecting two percent of the population over 65 years. Despite intensive research, the cause of the neuronal loss in PD is poorly understood.

Causes and extent of the problem: Recent research has implicated multiple cascade effects of neuroinflammation as pivotal contributing factors to neurodegeneration. However, the linkages between neuroinflammation, neurodegeneration and disease progression of Parkinson’s disease are poorly understood, often contradictory, and it is unclear whether neuroinflammation is a consequence of neurodegeneration or whether it causes neurodegenerative loss.

Extent and severity of problem: By the time of PD diagnosis, over 80% of dopaminergic neurons in the substantia nigra, have been lost, with the surviving 20% showing increased α-synuclein, intracellular proteinaceous inclusions and tau toxicity causing neuronal cell death.

Justification for research: Neurodegenerative changes in PD manifest as progressive muscle tremors, rigidity, impaired balance, slower stuttering movements, and verbal, visual and cognitive impairments dramatically impacting quality of life and shortening life expectancy. Currently there is no cure, damage is irreversible and medical treatment only slows the advancement of PD.

Elaboration of the issue: Neuroinflammatory causes can originate from protein misfolding, aggregation and accumulation, triggering gene mutation, increased microglial response linked to mitochondrial dysfunction and increased immune response in proinflammatory cytokine release (IL-1β). These changes are implicated in turning on the genes linked to increased oxidative stress and cellular toxicity associated with neuronal inflammation, apoptosis and neurodegenerative disease progression causing neurodegenerative diseases such as Parkinson’s.

Research aims: Currently the evidence between neuroinflammation and neurodegeneration is conflicting with no successful early bio-marker having been identified. This research aims to use human blood and plasma-based analysis to identify an early bio-marker of Parkinson’s disease by evaluating the mechanisms and potential causes of neuroinflammation as a trigger for neurodegeneration.

Methodology
Research based on human whole blood & plasma studies provided by Parkinson and control groups will be used to investigate mitochondrial dysfunction. Seahorse respirative oxidation experiments will evaluate inner and outer membrane malfunctioning, mtRNA misfolding, electron transfer chain damage, elevated levels of reactive oxygen species and their downstream cellular and membrane damage, proton leakage and identification of the membrane complexes involved in mitochondrial dysfunction. Genomic and proteomics will be utilised to identify gene mutations linked to neuroinflammation, neurodegeneration and Parkinson’s disease. Data generated during these experiments will be used to create bioinformatic databases for computational and multivariate statistical analysis to assist with identifying highly correlated gene and protein damage that can be used as a biomarker for neurodegeneration and early signs of Parkinson’s disease.

Research Advisory Panel
1. Clinical Advisor: Head of Neurology Department – Sunshine Hospital and Western Health
2. Mitochondria, Neurodegeneration and Parkinson’s Disease: Professor Paul Fisher, Research Fellow, Physiology Anatomy
& Microbiology, Latrobe University
3. Genomics, Proteomics and Genetic mutations: Dr Steve Petrovski, Senior lecturer in Genetics, Latrobe University
4. Neuroinflammation: Professor Stephen Kent, Head of School of Psychology and Public Health – advice includes aspects
of inflammation and neuroendocrinology.
5. Computational and multivariate statistics: Professor David Crewther, Head of Neuroscience and Human
Psychopharmacology, Swinburne University

Expected outcomes: The research results are expected to confirm the temporal progression of neuroinflammation as a cause of neurodegenerative disease, timing and severity, with results supporting further work into the development of early onset PD biomarkers allowing improved clinical and pharmacological treatments to slow, halt or reverse the impacts of neurogenerative progression. A successful biomarker will allow early intervention and modification of clinical, neurological and psychological therapies and medication programmes improving and potentially extending the patients quality and length of life in a more cost-effective way.

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