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Article ; Online: Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery.

Hull, Alexander / Atilano, Magda L / Gergi, Laith / Kinghorn, Kerri J

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2024 Volume 379, Issue 1899, Page(s) 20220381

Abstract: Impairment of autophagic-lysosomal pathways is increasingly being implicated in Parkinson's disease (PD). ...

Abstract	Impairment of autophagic-lysosomal pathways is increasingly being implicated in Parkinson's disease (PD).
MeSH term(s)	Animals ; Mice ; Parkinson Disease/drug therapy ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Gaucher Disease/drug therapy ; Gaucher Disease/genetics ; Gaucher Disease/metabolism ; Autophagy/genetics ; Lysosomes/genetics ; Lysosomes/metabolism ; Lysosomes/pathology ; Drug Discovery ; Immunity, Innate
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2022.0381
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Article: Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis.

Gray, Sophie C / Kinghorn, Kerri J / Woodling, Nathaniel S

Neural regeneration research

2020 Volume 15, Issue 7, Page(s) 1208–1219

Abstract: Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies ... ...

Abstract	Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer's disease is necessary. Recent studies have revealed increasing evidence for the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-established roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines produced by microglia in Alzheimer's disease. A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation may play a key role in the pathogenesis of Alzheimer's disease. Here we review recent findings on the roles played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer's disease. In each case, landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases, the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium, in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer's disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of the pathogenic mechanisms underlying Alzheimer's disease, and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer's disease brain.
Language	English
Publishing date	2020-02-11
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.272571
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Article ; Online: Pathological looping in the synucleinopathies: investigating the link between Parkinson's disease and Gaucher disease.

Kinghorn, Kerri J

Disease models & mechanisms

2011 Volume 4, Issue 6, Page(s) 713–715

MeSH term(s)	Animals ; Gaucher Disease/pathology ; Glucosylceramidase/metabolism ; Humans ; Lysosomes/drug effects ; Lysosomes/metabolism ; Models, Biological ; Parkinson Disease/pathology ; alpha-Synuclein/metabolism ; alpha-Synuclein/toxicity
Chemical Substances	alpha-Synuclein ; Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2011-09-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.008615
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Article ; Online: Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease.

Atilano, Magda L / Hull, Alexander / Romila, Catalina-Andreea / Adams, Mirjam L / Wildfire, Jacob / Ureña, Enric / Dyson, Miranda / Ivan-Castillo-Quan, Jorge / Partridge, Linda / Kinghorn, Kerri J

PLoS genetics

2023 Volume 19, Issue 12, Page(s) e1011063

Abstract: Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson's disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being ... ...

Abstract	Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson's disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread NF-kB signalling activation, including gut inflammation, and brain glial activation. We also demonstrate intestinal autophagic defects, gut dysfunction, and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, partially ameliorates lifespan, locomotor and immune phenotypes. Moreover, we show that modulation of the immune deficiency (IMD) pathway is detrimental to the survival of Gba1 deficient flies. We also reveal that direct stimulation of autophagy by rapamycin treatment achieves similar benefits to germ-free conditions independent of gut bacterial load. Consistent with this, we show that pharmacologically blocking autophagosomal-lysosomal fusion, mimicking the autophagy defects of Gba1 depleted cells, is sufficient to stimulate intestinal immune activation. Overall, our data elucidate a mechanism whereby an altered microbiome, coupled with defects in autophagy, drive chronic activation of NF-kB signaling in a Gba1 loss-of-function model. It also highlights that elimination of the microbiota or stimulation of autophagy to remove immune mediators, rather than prolonged immunosuppression, may represent effective therapeutic avenues for GBA1-associated disorders.
MeSH term(s)	Animals ; Gaucher Disease/genetics ; Gaucher Disease/metabolism ; Glucosylceramidase/genetics ; Drosophila/genetics ; Drosophila/metabolism ; Gastrointestinal Microbiome/genetics ; NF-kappa B/genetics ; Dysbiosis/genetics ; Parkinson Disease/genetics ; Autophagy/genetics
Chemical Substances	Glucosylceramidase (EC 3.2.1.45) ; NF-kappa B
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1011063
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Article: Mitochondrial dysfunction and defects in lipid homeostasis as therapeutic targets in neurodegeneration with brain iron accumulation.

Kinghorn, Kerri J / Castillo-Quan, Jorge Iván

Rare diseases (Austin, Tex.)

2016 Volume 4, Issue 1, Page(s) e1128616

Abstract: The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders ... ...

Abstract	The PLA2G6 gene encodes a group VIA calcium independent phospholipase A2 (iPLA2β), which hydrolyses glycerophospholipids to release fatty acids and lysophospholipids. Mutations in PLA2G6 are associated with a number of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia parkinsonism, collectively known as PLA2G6-associated neurodegeneration (PLAN). Recently Kinghorn et al. demonstrated in Drosophila and PLA2G6 mutant fibroblasts that loss of normal PLA2G6 activity is associated with mitochondrial dysfunction and mitochondrial lipid peroxidation. Furthermore, they were able to show the beneficial effects of deuterated polyunsaturated fatty acids (D-PUFAs), which reduce lipid peroxidation. D-PUFAs were able to rescue the locomotor deficits of flies lacking the fly ortholog of PLA2G6 (iPLA2-VIA), as well as the mitochondrial abnormalities in PLA2G6 mutant fibroblasts. This work demonstrated that the iPLA2-VIA knockout fly is a useful organism to dissect the mechanisms of pathogenesis of PLAN, and that further investigation is required to determine the therapeutic potential of D-PUFAs in patients with PLA2G6 mutations. The fruit fly has also been used to study some of the other genetic causes of NBIA, and here we also describe what is known about the mechanisms of pathogenesis of these NBIA variants. Mitochondrial dysfunction, defects in lipid metabolism, as well as defective Coenzyme A (CoA) biosynthesis, have all been implicated in some genetic forms of NBIA, including PANK2, CoASY, C12orf19 and FA2H.
Language	English
Publishing date	2016-01-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2817861-0
ISSN	2167-5511
ISSN	2167-5511
DOI	10.1080/21675511.2015.1128616
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Article: The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.

Kinghorn, Kerri J / Asghari, Amir M / Castillo-Quan, Jorge Iván

Neural regeneration research

2017 Volume 12, Issue 3, Page(s) 380–384

Abstract: Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in ... ...

Abstract	Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the
Language	English
Publishing date	2017-04-19
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.202934
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Article: Genetics and pharmacology of longevity: the road to therapeutics for healthy aging.

Castillo-Quan, Jorge Iván / Kinghorn, Kerri J / Bjedov, Ivana

Advances in genetics

2015 Volume 90, Page(s) 1–101

Abstract: Aging can be defined as the progressive decline in tissue and organismal function and the ability to respond to stress that occurs in association with homeostatic failure and the accumulation of molecular damage. Aging is the biggest risk factor for ... ...

Abstract	Aging can be defined as the progressive decline in tissue and organismal function and the ability to respond to stress that occurs in association with homeostatic failure and the accumulation of molecular damage. Aging is the biggest risk factor for human disease and results in a wide range of aging pathologies. Although we do not completely understand the underlying molecular basis that drives the aging process, we have gained exceptional insights into the plasticity of life span and healthspan from the use of model organisms such as the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Single-gene mutations in key cellular pathways that regulate environmental sensing, and the response to stress, have been identified that prolong life span across evolution from yeast to mammals. These genetic manipulations also correlate with a delay in the onset of tissue and organismal dysfunction. While the molecular genetics of aging will remain a prosperous and attractive area of research in biogerontology, we are moving towards an era defined by the search for therapeutic drugs that promote healthy aging. Translational biogerontology will require incorporation of both therapeutic and pharmacological concepts. The use of model organisms will remain central to the quest for drug discovery, but as we uncover molecular processes regulated by repurposed drugs and polypharmacy, studies of pharmacodynamics and pharmacokinetics, drug-drug interactions, drug toxicity, and therapeutic index will slowly become more prevalent in aging research. As we move from genetics to pharmacology and therapeutics, studies will not only require demonstration of life span extension and an underlying molecular mechanism, but also the translational relevance for human health and disease prevention.
MeSH term(s)	Aging/drug effects ; Aging/genetics ; Animals ; Antioxidants/administration & dosage ; Humans ; Longevity/drug effects ; Models, Animal ; Population Forecast ; Quality of Life ; United Nations
Chemical Substances	Antioxidants
Language	English
Publishing date	2015-07-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	148-x
ISSN	0065-2660
ISSN	0065-2660
DOI	10.1016/bs.adgen.2015.06.002
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Article: Agephagy - Adapting Autophagy for Health During Aging.

Stead, Eleanor R / Castillo-Quan, Jorge I / Miguel, Victoria Eugenia Martinez / Lujan, Celia / Ketteler, Robin / Kinghorn, Kerri J / Bjedov, Ivana

Frontiers in cell and developmental biology

2019 Volume 7, Page(s) 308

Abstract: Autophagy is a major cellular recycling process that delivers cellular material and entire organelles to lysosomes for degradation, in a selective or non-selective manner. This process is essential for the maintenance of cellular energy levels, ... ...

Abstract	Autophagy is a major cellular recycling process that delivers cellular material and entire organelles to lysosomes for degradation, in a selective or non-selective manner. This process is essential for the maintenance of cellular energy levels, components, and metabolites, as well as the elimination of cellular molecular damage, thereby playing an important role in numerous cellular activities. An important function of autophagy is to enable survival under starvation conditions and other stresses. The majority of factors implicated in aging are modifiable through the process of autophagy, including the accumulation of oxidative damage and loss of proteostasis, genomic instability and epigenetic alteration. These primary causes of damage could lead to mitochondrial dysfunction, deregulation of nutrient sensing pathways and cellular senescence, finally causing a variety of aging phenotypes. Remarkably, advances in the biology of aging have revealed that aging is a malleable process: a mild decrease in signaling through nutrient-sensing pathways can improve health and extend lifespan in all model organisms tested. Consequently, autophagy is implicated in both aging and age-related disease. Enhancement of the autophagy process is a common characteristic of all principal, evolutionary conserved anti-aging interventions, including dietary restriction, as well as inhibition of target of rapamycin (TOR) and insulin/IGF-1 signaling (IIS). As an emerging and critical process in aging, this review will highlight how autophagy can be modulated for health improvement.
Language	English
Publishing date	2019-11-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2019.00308
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Article: Gerontología molecular: hacia un envejecimiento saludable.

Castillo-Quan, Jorge Iván / Kinghorn, Kerri J

Gaceta medica de Mexico

2013 Volume 149, Issue 6, Page(s) 680–685

Abstract: For many years aging research was confined to statistics, psychology, and socioeconomic aspects of old age. However, today the study of aging is one of the most attractive and prosperous fields in biology. This change followed on from observations that ... ...

Title translation	Molecular gerontology: towards healthy aging.
Abstract	For many years aging research was confined to statistics, psychology, and socioeconomic aspects of old age. However, today the study of aging is one of the most attractive and prosperous fields in biology. This change followed on from observations that single gene mutations can modulate the aging process, demonstrating the dynamic and plastic nature of the pathways involved. The field of aging is continually being fuelled by the discovery of new genes and pathways that extend lifespan when manipulated in organisms ranging from unicellular yeast to the more complex round worm C. elegans and the fruit fly Drosophila melanogaster. Such interventions have also been successful in mammals, proving the principle that discoveries in invertebrates can be evolutionarily relevant to humans. The most successful and evolutionary conserved interventions are those related to nutrient sensing pathways, the effector pathways upon which dietary restriction operates to promote health and longevity. To validate the existence of genes that modify the aging process in humans, biogerontologists have opted for a genome-wide approach to studying centenarians, those fortunate to live beyond 100 years of age. By studying these individuals, they hope to unravel the genetic signatures that promote healthy ageing and long life.
MeSH term(s)	Aging/genetics ; Geriatrics ; Humans ; Insulin/physiology ; Insulin-Like Growth Factor I/physiology
Chemical Substances	Insulin ; Insulin-Like Growth Factor I (67763-96-6)
Language	Spanish
Publishing date	2013-11
Publishing country	Mexico
Document type	English Abstract ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	425456-9
ISSN	0016-3813
ISSN	0016-3813
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Article ; Online: A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.

Castillo-Quan, Jorge Iván / Tain, Luke S / Kinghorn, Kerri J / Li, Li / Grönke, Sebastian / Hinze, Yvonne / Blackwell, T Keith / Bjedov, Ivana / Partridge, Linda

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 42, Page(s) 20817–20819

Abstract: Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic ... ...

Abstract	Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in
MeSH term(s)	Aged ; Aging/drug effects ; Aging/metabolism ; Animals ; Drosophila/drug effects ; Drosophila/genetics ; Drosophila/growth & development ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drug Combinations ; Female ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/genetics ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Lithium/pharmacology ; Longevity/drug effects ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Middle Aged ; Nutrients/metabolism ; Pyridones/pharmacology ; Pyrimidinones/pharmacology ; Signal Transduction/drug effects ; Sirolimus/pharmacology
Chemical Substances	Drosophila Proteins ; Drug Combinations ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; Lithium (9FN79X2M3F) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2019-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1913212116
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