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Frontiers in Genetics 2022Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor...
Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer's disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.
PubMed: 36699460
DOI: 10.3389/fgene.2022.1012706 -
Cureus Dec 2020Alzheimer's disease (AD) is caused by several risk factors leading to dementia. It's diagnosis usually depends on clinical presentation and certain biomarkers in the... (Review)
Review
Alzheimer's disease (AD) is caused by several risk factors leading to dementia. It's diagnosis usually depends on clinical presentation and certain biomarkers in the cerebrospinal fluid (CSF). The brain has a high content of cholesterol and the metabolism of cholesterol in the brain can be associated with beta-amyloid plaques formation, which is seen in Alzheimer's disease. Given these implications, we studied if plasma lipid levels can vary in Alzheimer's disease and if these can be used as biomarkers to diagnose and predict the progression of Alzheimer's disease. Certain mutations in the brain cholesterol transport receptors and proteins and their association with Alzheimer's were also studied. This systematic review abides by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched multiple databases, such as Pubmed, Google Scholar, Pubmed central, ScienceDirect, Web of Science, and Medline with the help of keywords like Alzheimer's disease, cognitive impairment, plasma lipid biomarkers, cholesterol, brain cholesterol metabolism separately and in combination with each other. We collected 49 quality appraised articles on the association between plasma lipids and Alzheimer's disease and the genetic mutations in alleles related to cholesterol metabolism and Alzheimer's disease by applying the inclusion and exclusion criteria. Based on the finding of the studies reviewed, we found an association between plasma lipids, polymorphisms in genes associated with cholesterol transport, and Alzheimer's disease. Increased serum low-density lipoprotein (LDL-C), triglycerides (TG), total cholesterol (TC), sphingolipids, 24S hydroxycholesterol (24S-HC), 27O hydroxycholesterol (27O-HC) was associated with Alzheimer's. Decreased high-density lipoprotein (HDL-C) and phospholipids were noticed. Genetic mutations in apolipoprotein E (ApoE), apolipoprotein B (ApoB), apolipoprotein A (ApoA), ATP binding cassette transporter 1 (ABCA1), ATP binding cassette transporter 7 (ABCA7), amyloid precursor protein (APP), cytochrome P450 family 46 subfamilies A member 1 (CYP46A1), presenilin 1 (PSEN1), presenilin 2 (PSEN2) are also associated with increased risk of Alzheimer's disease. This study found an association between plasma lipids and Alzheimer's, proving that plasma lipids can be used as biomarkers for early diagnosis of Alzheimer's disease. It may also help predict the prognosis and stage the disease severity. Further studies are needed to find out the exact mechanism behind these changes.
PubMed: 33457117
DOI: 10.7759/cureus.12008 -
Dermatology (Basel, Switzerland) 2021Acne inversa/hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory disease of the skin that can significantly affect patients' quality of life. The etiology...
BACKGROUND
Acne inversa/hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory disease of the skin that can significantly affect patients' quality of life. The etiology and pathogenesis of HS are unclear and gene mutations might play a role.
SUMMARY
The primary focus of the review is on aggregating the gene mutations reported, summarizing the structure of γ-secretase and analyzing and speculating about the mechanism and the underlying relations between gene mutation and functional changes of protein. The systematic literature review was done by searching the PubMed, Embase, and Web of Science databases. γ-Secretase is an intramembrane protease complex responsible for the intramembranous cleavage of more than 30 type-1 transmembrane proteins including amyloid precursor protein and Notch receptors. The protein complex consists of four hydrophobic proteins: presenilin, presenilin enhancer-2 (PSENEN), nicastrin, and anterior pharynx defective 1 (APH1). To date, 57 mutations of γ-secretase genes have been reported in 70 patients or families worldwide, including 39 in NCSTN, 14 in PSENEN, and 4 in PSEN1, of which 17 are frameshifts, 15 result in nonsense mutations, 13 in missense mutations, and 12 are splice site mutations. Given the structure of γ-secretase and analysis of related mutation loci of NCSTN, PSENEN, and PSEN1, mutations in γ-secretase genes could affect activation of presenilin, prevent substrate binding, and hinder intramembrane cleavage of select proteins.
Topics: Amyloid Precursor Protein Secretases; Hidradenitis Suppurativa; Humans; Mutation
PubMed: 33333507
DOI: 10.1159/000512455 -
NeuroImage. Clinical 2020Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to... (Review)
Review
Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to investigate changes in white matter microstructure in Alzheimer's Disease. This paper aims to systematically review studies that examined the effect of Alzheimer's risk genes on white matter microstructure. We assimilated findings from 37 studies and reviewed their diffusion pre-processing and analysis methods. Most studies estimate the diffusion tensor (DT) and compare derived quantitative measures such as fractional anisotropy and mean diffusivity between groups. Those with increased AD genetic risk are associated with reduced anisotropy and increased diffusivity across the brain, most notably the temporal and frontal lobes, cingulum and corpus callosum. Structural abnormalities are most evident amongst those with established Alzheimer's Disease. Recent studies employ signal representations and analysis frameworks beyond DT MRI but show that dMRI overall lacks specificity to disease pathology. However, as the field advances, these techniques may prove useful in pre-symptomatic diagnosis or staging of Alzheimer's disease.
Topics: Alzheimer Disease; Anisotropy; Brain; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Humans; White Matter
PubMed: 32758801
DOI: 10.1016/j.nicl.2020.102359