ORCID Profile
0000-0003-4689-1198
Current Organisation
University of Tasmania
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Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.BRAINRESBULL.2016.07.012
Abstract: Neurofilaments are major protein constituents of the brain, but are particularly abundant in specific subpopulations of neurons and likely have a key role in the regulation of axonal calibre. Neurofilament proteins may also be involved in the transformation of the neuronal cytoskeleton leading to substantial tau pathology in axons damaged by Aβ, subsequently leading to neurofibrillary pathology in their cell bodies of origin. An understanding of neurofilamentous changes in axons and subsequent tau pathology may provide insight into how Aβ pathology may stimulate an aberrant plasticity-related response of damaged neurons, leading to the progressive and degenerative changes in the neuronal cytoskeleton that result in synapse loss and neuronal degeneration.
Publisher: Frontiers Media SA
Date: 03-04-2019
Publisher: Springer Science and Business Media LLC
Date: 03-01-2021
Publisher: Cold Spring Harbor Laboratory
Date: 29-08-2023
DOI: 10.1101/2023.08.28.555025
Abstract: The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the erse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One dichotomy emerging in the field is that protection of the neuronal cell soma itself does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of in idual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a potential mechanism to stabilise axons and prevent axonal loss and neurodegeneration in ALS. This study has utilized an orally dosed HDAC6 specific inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Furthermore, co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in the lumbar spinal cord of female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.11.467877
Abstract: Neurons live for the lifespan of the in idual and underlie our ability for lifelong learning and memory. However, aging alters neuron morphology and function resulting in age-related cognitive decline. It is well established that epigenetic alterations are essential for learning and memory, yet few neuron-specific genome-wide epigenetic maps exist into old age. Comprehensive mapping of H3K4me3 and H3K27ac in mouse neurons across lifespan revealed plastic H3K4me3 marking that differentiates neuronal age linked to known characteristics of cellular and neuronal aging. We determined that neurons in old age recapitulate the H3K27ac enrichment at promoters, enhancers and super enhancers from young adult neurons, likely representing a re-activation of pathways to maintain neuronal output. Finally, this study identified new characteristics of neuronal aging, including altered rDNA regulation and epigenetic regulatory mechanisms. Collectively, these findings indicate a key role for epigenetic regulation in neurons, that is inextricably linked with aging.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEUROBIOLAGING.2016.05.003
Abstract: There is increasing evidence that epigenetic alterations may play a role in Alzheimer's disease (AD) yet, there is little information regarding epigenetic modifications in specific cell types. We assessed DNA methylation (5-methylcytosine [5mC]) and hydroxymethylation (5-hydroxymethylcytosine [5hmC]) marks specifically in neuronal and glial cell types in the inferior temporal gyrus of human AD cases and age-matched controls. Interestingly, neurofilament (NF)-labeled pyramidal neurons that are vulnerable to AD pathology are deficient in extranuclear 5mC in AD cases compared with controls. We also found that fewer astrocytes exhibited nuclear 5mC and 5hmC marks in AD cases compared with controls. However, there were no alterations in 5mC and 5hmC in disease-resistant calretinin interneurons or microglia in AD, and there was no alteration in the density of 5mC- or 5hmC-labeled nuclei in near-plaque versus plaque-free regions in late-AD cases. 5mC and 5hmC were present in a high proportion of neurofibrillary tangles, suggesting no loss of DNA methylation marks in tangle bearing neurons. We provide evidence that epigenetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD.
No related grants have been discovered for Andrew Phipps.