Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases

Ejlerskov, Patrick; Ashkenazi, Avraham; Rubinsztein, David C.

doi:10.1016/j.nbd.2018.04.001

Cited by 15 publications

(11 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The significant evidence linking autophagy and tauopathies has generated interest in developing autophagy-based therapeutics, and studies so far have indicated promising therapeutic potential in Alzheimer's disease and various tauopathies 5,39,40 . Autophagy stimulation may be performed either chemically using small molecule enhancers of autophagy or through gene therapy approaches.…”

Section: Autophagy Inducers In Alzheimer's Diseasementioning

confidence: 99%

“…Small molecule enhancers of autophagy may be split in two main categories based on their mechanism of action: mTOR-dependent or mTOR-independent 1,21,39 . The first category of autophagy-inducing compounds is composed of mTOR inhibitors, including rapamycin and other rapalogs.…”

Section: Autophagy Inducers In Alzheimer's Diseasementioning

confidence: 99%

“…For many tauopathies, upregulation of autophagy may be an attractive therapeutic strategysuccessful autophagy induction and improved neurodegeneration phenotypes were seen in various in vivo models 1,39,78 . However, diseases with impairment in the late stages of autophagy and lysosomal functioning may not benefit from further activation of autophagy.…”

Section: Genetic Approaches In Alzheimer's Diseasementioning

confidence: 99%

See 2 more Smart Citations

Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

Djajadikerta

Keshri

Pavel

et al. 2020

Journal of Molecular Biology

Self Cite

174

View full text Add to dashboard Cite

 Autophagy delivers cytoplasmic cargoes to lysosomes for degradation  It degrades many aggregate-prone proteins responsible for neurodegenerative disease  Enhancing autophagy has therapeutic potential in common neurodegenerative diseases  Evidence in cells and in vivo demonstrates promising results in many disease models  Outcomes may depend on how autophagy impacts disease pathogenesis

show abstract

Section: Autophagy Inducers In Alzheimer's Diseasementioning

confidence: 99%

Section: Autophagy Inducers In Alzheimer's Diseasementioning

confidence: 99%

Section: Genetic Approaches In Alzheimer's Diseasementioning

confidence: 99%

See 1 more Smart Citation

Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

Djajadikerta

Keshri

Pavel

et al. 2020

Journal of Molecular Biology

Self Cite

174

View full text Add to dashboard Cite

show abstract

“…In response to stress, autophagy pathways mediate the degradation of cellular components; organelles, as well as lipids and proteins, to generate nutrients and metabolic building blocks to maintain cellular homeostasis ( Dikic and Elazar, 2018 ; Ejlerskov et al, 2018 ). Autophagic processes in post-mitotic cells such as neurons, cardiac myocytes, and retinal pigment epithelium (RPE), are essential for cellular quality control, as these cells are unable to decrease their load of damaged organelles, accumulated lipids or protein aggregates through cell division ( Boya et al, 2016 ; Liang and Sigrist, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Dhingra

Bell

Peachey

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Like other neurons, retinal cells utilize autophagic pathways to maintain cell homeostasis. The mammalian retina relies on heterophagy and selective autophagy to efficiently degrade and metabolize ingested lipids with disruption in autophagy associated degradation contributing to age related retinal disorders. The retinal pigment epithelium (RPE) supports photoreceptor cell renewal by daily phagocytosis of shed photoreceptor outer segments (OS). The daily ingestion of these lipid-rich OS imposes a constant degradative burden on these terminally differentiated cells. These cells rely on Microtubule-Associated Protein 1 Light Chain 3 (LC3) family of proteins for phagocytic clearance of the ingested OS. The LC3 family comprises of three highly homologous members, MAP1LC3A (LC3A), MAP1LC3B (LC3B), and MAP1LC3C (LC3C). The purpose of this study was to determine whether the LC3B isoform plays a specific role in maintaining RPE lipid homeostasis. We examined the RPE and retina of the LC3B-/- mouse as a function of age using in vivo ocular imaging and electroretinography coupled with ex vivo, lipidomic analyses of lipid mediators, assessment of bisretinoids as well as imaging of lipid aggregates. Deletion of LC3B resulted in defects within the RPE including increased phagosome accumulation, decreased fatty acid oxidation and a subsequent increase in RPE and sub-RPE lipid deposits. Age-dependent RPE changes included elevated levels of oxidized cholesterol, deposition of 4-HNE lipid peroxidation products, bisretinoid lipofuscin accumulation, and subretinal migration of microglia, collectively likely contributing to loss of retinal function. These observations are consistent with a critical role for LC3B-dependent processes in the maintenance of normal lipid homeostasis in the aging RPE, and suggest that LC3 isoform specific disruption in autophagic processes contribute to AMD-like pathogenesis.

show abstract

“…Besides its role in the APP cleavage to Aβ as part of the γ-secretase complex, PS1 regulates N-glycosylation of the V-ATPase subunit V o A1 essential for lysosomal acidification and subsequent degradation of autophagic content. Abnormally increased levels of acid sphingomyelinase (SMase) in AD brains lower TFEB levels by promoting its proteolysis [30] . Conversely, chemical inhibition of this SMase with amitriptyline increased the degradation of p62 and LC3-II, and delayed the disease development in APP/PS1 mouse models of AD [17,30] .…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Autophagy in ageing and ageing-related neurodegenerative diseases

Karabiyik¹,

Frake²,

Park³

et al. 2021

AND

Self Cite

View full text Add to dashboard Cite

Autophagy is a catabolic mechanism that allows cells to deliver cytoplasmic contents to lysosomes for degradation to maintain energy homeostasis and to protect cells against stress. Autophagy has been directly linked to neurodegeneration and ageing by an extensive body of research. It has become evident that disruption of autophagy contributes significantly to age-related pathologies and to the cognitive and motor declines associated with "healthy" ageing. Autophagic dysfunction causes the accumulation of many of the toxic, aggregate-prone proteins that are responsible for neurodegenerative diseases, including mutant huntingtin, alpha-synuclein, tau, and others. Since upregulation of autophagy has been found to reduce levels of such protein species, the therapeutic potential of autophagy induction as a strategy against age-related diseases and a method for modulating longevity has been widely studied. Here we review the evidence supporting a role for autophagy dysfunction in the progression of the age-associated functional decline in the brain and age-related brain pathologies and discuss the available evidence that upregulation of autophagy may be a valuable therapeutic strategy.

show abstract

Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases

Cited by 15 publications

References 76 publications

Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

Microtubule-Associated Protein 1 Light Chain 3B, (LC3B) Is Necessary to Maintain Lipid-Mediated Homeostasis in the Retinal Pigment Epithelium

Autophagy in ageing and ageing-related neurodegenerative diseases

Contact Info

Product

Resources

About