18 research outputs found
A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration
published_or_final_versio
Differential roles of the ubiquitin-proteasome system and autophagy in experimental models of Alzheimerās disease.
Conference Theme: Nature and Nurture in Brain FunctionsAlzheimerās disease (AD) is a progressive neurodegenerative disease and most prevalent form of dementia today. Current therapeutics are only capable of alleviating symptoms without targeting the root of the problem, as the pathogenesis of AD is still not completely clear. As pathological hallmarks of AD include the accumulation of Ī²-amyloid (AĪ²) and hyperphosphorylated tau protein aggregates, the current study examines whether impairments in protein degradation pathways, namely the ubiquitin-proteasome system and autophagy-lysosomal pathway, may play important roles in contributing to AD pathogenesis. Using primary cortical neuronal culture exposed to oligomeric AĪ² as an in vitro model and triple transgenic (3xTg) AD mice as an in vivo model, this study examines longitudinal changes in protein degradation pathways and its relationship to tau accumulation and aggregation. How modulations of ubiquitin, a signaling protein involved in both proteasomal and autophagic degradation of target proteins, can mediate tau expression and aggregation was also explored. An initial impairment in proteasomal activity with a subsequent activation of the autophagy-lysosomal pathway was found both in vitro and in vivo. This corresponded with the changes in lysine residue 48 and 63- specific ubiquitin expression, which signals for proteasome and autophagic degradation of target proteins, respectively. Impairments in protein degradation resulted in an accumulation and aggregation of phosphorylated and non-phosphorylated forms of tau with the expression of ubiquitin mutants signaling for autophagic degradation attenuating this accumulation. In conclusion, this study shows the progression of the decline in proper protein degradation both in vitro and in vivo with modulation in ubiquitin signaling as a possible new therapeutic target for AD
Investigating protein degradation pathways in Alzheimer's disease
Abstracts from AAIC 2016 will be published in a future issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Associatio
The effect of oxyresveratrol on endoplasmic reticulum stress in Parkinson's disease
Conference Theme: Nature and Nurture in Brain FunctionsParkinsonās disease (PD) results from a loss of dopaminergic neurons and the presence of intracytoplasmic inclusions
known as Lewy bodies (LB), culminating in a loss of motor function. While the risk factors are multifactorial in nature,
there is no breakthrough curative therapy for PD. Oxyresveratrol (OXY) is a potent antioxidant found in Mulberry fruits.
We have previously reported the neuroprotective potential of OXY in an in vitro parkinsonian model. The aim of this study
is to investigate the effects of OXY on specific pathways implicated in PD.
Human neuroblastoma SH-SY5Y cells were stably transfected to express the A30P familial mutant of alpha synuclein (Ī±S),
which is the main constituent of LBs. Forty eight hours after treatment with OXY, we observed a reduction in the misfolded,
oligomeric species of Ī±S. A build-up of misfolded protein leads to stress in the endoplasmic reticulum (ER), subsequently
activating the unfolded protein response (UPR). Therefore, our next aim was to study the effects of OXY on this
pathological pathway in a PD model. SH-SY5Y cells were treated with 6-hydroxydopamine, a parkinsonian mimetic toxin,
after pre-treatment with OXY. Activation of signaling molecules involved in the UPR were then assessed. The results
showed that OXY does indeed modulate the UPR, in turn mitigating ER stress. This gives us an idea of the underlying
mechanism by which OXY exerts neuroprotective effects in PD.
The study is supported by Health and Medical Research Fund 02131496
Environmental pollutants as risk factos for developing cognitive dysfunctions and Alzheimerās disease
The dynamic mitochondrial network in Alzheimer's disease
Abstracts from AAIC 2016 will be published in a future issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Associatio
Investigating the effects of silica nanoparticles on neurodegeneratioive-like changes in behaviors and neuropathology.
The dynamic mitochondria network in neurodegeneration
Conference Theme: Nature and Nurture in Brain FunctionsMitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and
apoptosis in neurodegeneration. It is traditionally believed that once the morphology of mitochondria shifts away from its
physiological tubular form, mitochondria becomes defective and downstream apoptotic signalling pathways are triggered.
In this study, we explored the dynamic changes in mitochondrial network in neurodegeneration.
Our study showed that at early stages of neurodegeneration, beta-amyloid (Ab ) induced morphological changes in
mitochondria where they become granular shape which was distinct from the conventional round and fragmented
mitochondria in terms of both morphology and function. In addition, we demonstrated that accumulation of mitochondrial
reactive oxygen species triggered granular mitochondria formation, while mitoTEMPO (a mitochondria-targeted
superoxide scavenger) restored tubular mitochondrial morphology within Ab -treated neurons. Interestingly, modulations
of mitochondria fission and fusion by genetic and pharmacological means not only attenuated the induction of granular
mitochondria but also diminished mitochondrial superoxide levels in Ab -treated neurons.
This study demonstrates a unique reciprocal relationship between mitochondrial dynamics and reactive oxygen species and
provides a new possible therapeutic target at early stages of neurodegenerative disease pathogenesis. This study is supported
by HMRF02131956, HKU Alzheimerās Disease Research Network, and generous donation from Ms. Kit-Wan Chow
The role of oxyresveratrol in mitigating cellular toxicity in Parkinsonās disease
Conference Theme: Science and Aging: An Era of discover
Investigation of drugs targeting mitochondrial dynamics and reactive oxygen species for Parkinsonās disease treatment
Conference Theme: Science and Aging: An Era of discover