Evidence for autophagic gridlock in aging and neurodegeneration

Bakhoum, Mathieu F.; Bakhoum, Christine Y; Ding, Zenghui; Carlton, Susan M.; Campbell, Gerald A.; Jackson, George R.

doi:10.1016/j.trsl.2014.01.016

Cited by 14 publications

(14 citation statements)

References 47 publications

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“…Tau aggregates are degraded through autophagy pathway (Wang and Mandelkow, 2012; Ji et al, 2017). Autophagic gridlock also contributes to the development of AD-like tauopathy (Bakhoum et al, 2014). The abundance of AVs in the brains of AD animal models and AD patients is in sharp contrast to the rarely-observed AVs in normal brains, which suggests that the accumulation of pathogenic proteins such as Aβ and tau in AD may be caused by defective autophagy-lysosome proteolysis pathway (Cataldo et al, 2004; Yang et al, 2011a).…”

Section: Malfunction Of Autophagy In Admentioning

confidence: 99%

Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Liu

2019

Front. Mol. Neurosci.

127

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Alzheimer’s disease (AD) is the most common type of dementia which characterized by a progressive loss of memory and cognitive function due to degeneration of synapses and axons. Currently, there is no cure for AD. Deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs) are two hallmark pathologic changes in the brains of Alzheimer’s patients. Autophagy is the major mechanism in cells responsible for removing protein aggregates. Accumulation of immature autophagic vacuoles (AVs) in dystrophic neurites of Alzheimer patients’ brains suggests that autophagy process is disrupted. Till now, it is far from clear what role autophagy plays in AD, a causative role, a protective role, or just a consequence of the disease process itself. To design more effective therapeutic strategies towards this devastating disorder, it is essential to understand the exact role of autophagy played during different stages of AD.

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Section: Malfunction Of Autophagy In Admentioning

confidence: 99%

Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Liu

2019

Front. Mol. Neurosci.

127

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“…In addition, p62, which is a part of the ubiquitin proteasome system, has been identified to directly bind with TDP-43, and its overexpression can reduce TDP-43 aggregation (Tanji et al 2012). Previously, we showed that misexpression of Tau leads to dysfunction of the autophagic process and leads to formation of giant autophagic bodies (Bakhoum et al 2014). Similar to our previous findings, these acidic lysosomal vacuoles observed in codon-optimized TDP-43 model were mature autolysosomes induced to clear the cytoplasmic aggregates of TDP-43.…”

Section: Discussionmentioning

confidence: 99%

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Yusuff

Chatterjee

Chang

et al. 2019

Preprint

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59Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration 60 associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The 61 exact mechanism by which TDP-43 exerts toxicity in the brains of affected patients remains unclear. In 62 a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of 63 insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary 64 GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue 65 specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized 66 transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, 67 exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and 68 cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in 69 the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are 70 characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to 71 form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to 72 activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 73model is an excellent resource that could be used in genetic screens to identify and better understand the 74 exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets. 75 76 77 78 79 80 4 103 5 (Johnson et al.

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“…A second mechanism of toxicity that has emerged from studies conducted in the fly eye is autophagy, an important element of normal cell physiology that is implicated in a number of neurogenerative disorders. Bakhoum et al (2014) used the fly eye to show that autophagy could play a role in tauopathies. They found that misexpression of htau induced accumulation of autophagic intermediates with large vacuoles, termed giant autophagic bodies (GABs), which are indicative of autophagic dysfunction.…”

Section: Cellular Mechanisms For Tau Toxicity and Dysfunction In The mentioning

confidence: 99%

An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer’s disease

Sivanantharajah

Mudher

Shepherd

2019

Journal of Neuroscience Methods

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Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's Disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tautoxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.

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Evidence for autophagic gridlock in aging and neurodegeneration

Cited by 14 publications

References 47 publications

Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Targeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer’s disease

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