Astrocytes and lysosomal storage diseases

Rao, Kakulavarapu V. Rama; Kielian, Tammy

doi:10.1016/j.neuroscience.2015.05.061

Cited by 30 publications

(37 citation statements)

References 170 publications

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“…The NCLs, like many other lysosomal storage diseases, are characterized by astrogliosis, as indicated by increased amounts of glial fibrillary acid protein (GFAP) in astrocytes . Examination of the cerebellar cortex from Australian Cattle Dog A by immunohistochemistry disclosed very high numbers of cells in both the cerebellar medulla and the granule cell layer that stained strongly with an anti‐GFAP antibody (Fig A and C).…”

Section: Resultsmentioning

confidence: 98%

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies

Kolicheski

Johnson

O’Brien

et al. 2016

Veterinary Internal Medicne

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BackgroundNeuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative disease, has been diagnosed in young adult Australian Cattle Dogs.ObjectiveCharacterize the Australian Cattle Dog form of NCL and determine its molecular genetic cause.AnimalsTissues from 4 Australian Cattle Dogs with NCL‐like signs and buccal swabs from both parents of a fifth affected breed member. Archived DNA samples from 712 individual dogs were genotyped.MethodsTissues were examined by fluorescence, electron, and immunohistochemical microscopy. A whole‐genome sequence was generated for 1 affected dog. A TaqMan allelic discrimination assay was used for genotyping.ResultsThe accumulation of autofluorescent cytoplasmic storage material with characteristic ultrastructure in tissues from the 4 affected dogs supported a diagnosis of NCL. The whole‐genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T. All 4 DNA samples from clinically affected dogs tested homozygous for the variant allele. Both parents of the fifth affected dog were heterozygotes. Archived DNA samples from 346 Australian Cattle Dogs, 188 Border Collies, and 177 dogs of other breeds were homozygous for the reference allele. One archived Australian Cattle Dog sample was from a heterozygote.Conclusions and Clinical ImportanceThe homozygous CLN5 nonsense is almost certainly causal because the same mutation previously had been reported to cause a similar form of NCL in Border Collies. Identification of the molecular genetic cause of Australian Cattle Dog NCL will allow the use of DNA tests to confirm the diagnosis of NCL in this breed.

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Section: Resultsmentioning

confidence: 98%

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies

Kolicheski

Johnson

O’Brien

et al. 2016

Veterinary Internal Medicne

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“…Similarly, enlarged mitochondria were observed in a neuronal cerebellar granular cell line derived from JNCL mice . Although astrocytic mitochondrial dysfunction in NCL has not yet been reported, it should be noted that astrocyte activation is observed in all NCL forms, and mitochondrial dysfunction is a common denominator in reactive astrocytes, suggesting a potential link between the two (see).…”

Section: Potential Factors That Disrupt Neuron‐astrocyte Interactionsmentioning

confidence: 99%

“…NCLs are associated with neuronal loss in select brain regions, including the hippocampus, thalamus and various cortical areas . Additionally, astrocyte activation is evident in each NCL form . In JNCL mouse models, studies have shown early prominent astrocyte activation, as indicated by increased GFAP expression, that precedes neuronal loss in these mice that does not occur until 12 months‐of‐age .…”

Section: Introductionmentioning

confidence: 99%

Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

Rao

Kielian

2015

Clinical & Exp Neuroim

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Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron–astrocyte cross-talk in the context of select neurodegenerative diseases.

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“…Inflammatory processes occurring within CNS (by glial cells) contribute vulnerability by initiating vascular damage (Doyle et al, 2015, Weaver et al, 2010) neurological insult (Bodnar et al, 2015, Garcia et al, 2016) and destruction to the blood brain barrier (BBB). (Adelson et al, 1998) While CNS glial cells exert an influential role in neurodevelopment, neuronal homeostasis and CNS detoxification, on the flip side, detrimental inflammatory processes can arise from head trauma (Lopez-Rodriguez et al, 2015), ischemia (Li et al, 2015c) infection (Ben Haim et al, 2015a) lysosomal storage diseases (Rama Rao and Kielian, 2015) and protein aggregates of amyloid β (Aβ) (Ben Haim, Carrillo-de Sauvage, 2015a) and α-synuclein A53T (Ben Haim, Carrillo-de Sauvage, 2015a, Yang et al, 2015) common to AD and PD, respectively. Once neurodegeneration ensues, reactive gliosis (Mohn and Koob, 2015) circumscribing degenerative neurons can occur due to debris generated as danger-associated molecular patterns (DAMPs), (Frank et al, 2016, Kigerl et al, 2014) leading to a cyclic perpetuated release of pro-inflammatory neurotoxic cytokines (Hammond et al, 2015, Mohn and Koob, 2015).…”

Section: Introductionmentioning

confidence: 99%

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

Mazzio

Bauer

Mendonca

et al. 2017

Journal of Neuroimmunology

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Chronic or acute central nervous system (CNS) inflammation is carried out by glial cells, which can contribute to neurological injuries associated with head trauma, stroke, and infection, Parkinson’s or Alzheimer ’s disease. The process of aging combined with inflammation are also risk factors for developing glioblastoma multiforme (GBM) as well as perpetuating its malignant aggression. With growing public curiosity in complementary and alternative medicines (CAMs), in this work we conduct a high throughput (HTP) screening of >1400 natural herbs, plants and over the counter (OTC) products for anti-inflammatory effects on lipopolysaccharide (LPS)/interferon gamma (IFNγ) activated C6 glioma cells. Validation studies suggest a pro-inflammatory profile mediated by LPS [3μg/ml/IFNγ 3ng/ml] is consistent with elevation [> 8.5 fold] of MCP-1 and cytokine-induced neutrophil chemo-attractants (CINC) 1, CINC 2a and CINC3. The data show no evidence of changes to the following, IL-13, TNF-a, fracktaline, leptin, LIX, GM-CSF, ICAM1, L-Selectin, activin A, agrin, IL-1α, MIP-3a, B72/CD86, NGF, IL-1b, MMP-8, IL-1 R6, PDGF-AA, IL-2, IL-4, prolactin R, RAGE, IL-6, Thymus Chemokine-1, CNTF,IL-10 or TIMP-1. The data also show a LPS/IFNγ mediated rise in iNOS and NO2− as often reported. A HTP screening was conducted, where we employ an in vitro efficacy index (iEI) defined as the ratio of toxicity (LC50)/anti-inflammatory potency (IC50) to ensure biological effects were occurring in fully viable cells (ratio > 3.8). Using NO2− as a guideline molecule, the data show that 1.77 % (25 of 1410 tested) (at <250μg/ml) had anti-inflammatory effects with an iEI ratio >3.8. These include reference drugs (hydrocortisone, dexamethasone N6-(1-iminoethyl)-L-lysine and NSAIDS : diclofenac, tolfenamic acid), a histone deacetylase inhibitor (apicidin) and the following natural products; Ashwaganda (Withania somnifera), Elecampagne Root (Inula helenium), Feverfew (Tanacetum parthenium), Green Tea (Camellia sinensis), Turmeric Root (Curcuma Longa) Ganthoda (Valeriana wallichii), Tansy (Tanacetum vulgare), Maddar Root (Rubia tinctoria), Red Sandle wood (Pterocarpus santalinus), Bay Leaf (Laurus nobilis, Lauraceae), quercetin, cardamonin, fisetin, EGCG, biochanin A, galangin, apigenin and curcumin. The herb with the largest iEI was Ashwaganda where the IC50/LC50 was 11.1/>1750.0 μg/mL, and the compound with the greatest iEI was quercetin where the IC50/LC50 was 10.0/>363.6 ug/mL. These substances also downregulate the production of iNOS expression and attenuate CINC-3 release. In summary, this HTP screening provides guideline information as to efficacy of natural products that in the long term, could prevent inflammatory processes associated with neurodegenerative disease and aggressive glioma tumor growth.

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Astrocytes and lysosomal storage diseases

Cited by 30 publications

References 170 publications

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies

Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

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