International Journal of Molecular Sciences

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Dr. Adonis Sfera

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1. Paton State Hospital, 3102 Highland Ave, Patton, CA 92369, USA
2. Department of Psychiatry, University of California, Riverside 900 University Ave, Riverside, CA 92521, USA
3. School of Behavioral Health, Loma Linda University, 11139 Anderson St., Loma Linda, CA 92350, USA
Interests: neurocognitive disorders; schizophrenia; molecular biology; neurolipidomics
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Dear Colleagues,

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, place a heavy burden on global healthcare facilities worldwide. But, the relationship between physiological aging and neurodegenerative disorders is complex and poorly defined at present. After the completion of the human genome project, many questions remain unanswered. What is the evolutionary advantage of aging? Is neurodegeneration the result of increased longevity? How does the environment contribute to neurodegeneration? What happens at the genome/epigenome interface? Is this the time to develop novel paradigms and markers for neurodegenerative disorders?

Human genetics provides unbiased insights into the causes of monogenic disorders and human diseases and provides help in approaching complex conditions, facilitating more accurate diagnoses. But, the extrapolation of preclinical observations into meaningful clinical data that can clarify the etiopathogenesis of age-related disorders is laborious and complex, and this challenge, in particular, has slowed the development of interventions for neurodegenerative disease.

This Special Issue aims to attract high-quality studies on the relationship between gene variations and clinical features of neurodegenerative diseases. We will strive to present a cohesive picture of the state of the art in the field and help to advance our understanding and management of neurodegenerative diseases. The topics we would like to cover include, but are not limited to:

The genetic background of Parkinson’s disease dementia and Lewy body dementia;
The whole-genome multi-omics profiling of diseased and healthy brains;
GWAS for disease endophenotypes;
Mechanistic insights into the function of disease-established key genes, including APOE, SNCA, and LRRK2;
Neurodegeneration in rare diseases (ex. progeria) and infectious etiologies;
The role of epigenetic mechanisms in the context of neurodegenerative diseases;
Gene therapy approaches such as ASO and genome editing.

Dr. Adonis Sfera
Guest Editor

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Keywords

neurodegenerative disorders
redox systems
proteostasis
seeding misfolded proteins
antimicrobial peptides
epigenome

Published Papers (2 papers)

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Research

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25 pages, 4816 KiB

Open AccessArticle

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS

by Marwa Zafarullah, Jie Li, Michelle R. Salemi, Brett S. Phinney, Blythe P. Durbin-Johnson, Randi Hagerman, David Hessl, Susan M. Rivera and Flora Tassone

Int. J. Mol. Sci. 2023, 24(17), 13477; https://doi.org/10.3390/ijms241713477 - 30 Aug 2023

Cited by 2 | Viewed by 991

Abstract

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS. Full article

(This article belongs to the Special Issue Genomics in Neurodegenerative Diseases)

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Review

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18 pages, 1931 KiB

Open AccessReview

Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

by Adonis Sfera, Leah Rahman, Carlos Manuel Zapata-Martín del Campo and Zisis Kozlakidis

Int. J. Mol. Sci. 2023, 24(16), 12648; https://doi.org/10.3390/ijms241612648 - 10 Aug 2023

Cited by 3 | Viewed by 3975

Abstract

Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called “brain fog”, affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell–cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the “seeding” of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood–brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation. Full article

(This article belongs to the Special Issue Genomics in Neurodegenerative Diseases)

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