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Neurodegenerative Diseases: From Molecular Basis to Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 38614

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Special Issue Editors

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy
Interests: multiple sclerosis; neurodegeneration; dementia; vitamin D; cerebrospinal fluid biomarkers; molecular and cellular neuroscience
Special Issues, Collections and Topics in MDPI journals
University of Palermo, Department of Biomedicine, Neuroscience, and advanced diagnostics, Institute of Clinical Biochemistry and Clinical Laboratory Medicine
Interests: BIoamrkers; laboratory medicine; sepsis; cardiovascular disease; machine learning; neurological diseases; Alzheimer's disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases (NDs) are a heterogeneous group of complex diseases, characterized by neuronal loss and progressive degeneration of different areas of the nervous system. NDs represent a major health problem worldwide, with an increasing incidence rate. Although the exact pathogenesis of NDs remains unclear, a complex interaction between genetic, epigenetic and environmental factors has been proposed. To date, no effective therapeutics have been developed to slow, halt or prevent any NDs. Thus, information on the molecular mechanisms underlying the pathogenesis of NDs is strongly sought after.

The aim of the current Special Issue is to describe the advances in the field of NDs, including Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis and Parkinson’s disease, with a focus on the underlying pathobiological mechanisms.

We would like to invite you to submit original research articles and reviews on, but not limited to, new findings on molecular key players, pathomechanisms, risk factors, biomarkers and therapeutic targets of NDs.

Prof. Dr. Marcello Ciaccio
Dr. Luisa Agnello
Guest Editors

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Keywords

  • genetic
  • biomarkers
  • Alzheimer’s disease
  • multiple sclerosis
  • amyotrophic lateral sclerosis
  • neurodegenerative diseases

Published Papers (12 papers)

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Editorial

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3 pages, 190 KiB  
Editorial
Neurodegenerative Diseases: From Molecular Basis to Therapy
by Luisa Agnello and Marcello Ciaccio
Int. J. Mol. Sci. 2022, 23(21), 12854; https://doi.org/10.3390/ijms232112854 - 25 Oct 2022
Cited by 13 | Viewed by 2219
Abstract
Neurodegenerative diseases (NDs) are a heterogeneous group of complex diseases characterized by neuronal loss and progressive degeneration of different areas of the nervous system [...] Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)

Research

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17 pages, 3738 KiB  
Article
Non-Apoptotic Caspase-3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum
by Tim Fieblinger, Chang Li, Elena Espa and M. Angela Cenci
Int. J. Mol. Sci. 2022, 23(10), 5470; https://doi.org/10.3390/ijms23105470 - 13 May 2022
Cited by 8 | Viewed by 2113
Abstract
Non-apoptotic caspase-3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase-3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence [...] Read more.
Non-apoptotic caspase-3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer’s disease. It is, however, not known whether caspase-3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson’s disease, we provide the first evidence that caspase-3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase-3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long-term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non-apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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18 pages, 2876 KiB  
Article
Neuroprotective Effect of Luteolin-7-O-Glucoside against 6-OHDA-Induced Damage in Undifferentiated and RA-Differentiated SH-SY5Y Cells
by Stephanie Cristine Hepp Rehfeldt, Joana Silva, Celso Alves, Susete Pinteus, Rui Pedrosa, Stefan Laufer and Márcia Inês Goettert
Int. J. Mol. Sci. 2022, 23(6), 2914; https://doi.org/10.3390/ijms23062914 - 08 Mar 2022
Cited by 16 | Viewed by 3066
Abstract
Luteolin is one of the most common flavonoids present in edible plants and its potential benefits to the central nervous system include decrease of microglia activation, neuronal damage and high antioxidant properties. The aim of this research was to evaluate the neuroprotective, antioxidant [...] Read more.
Luteolin is one of the most common flavonoids present in edible plants and its potential benefits to the central nervous system include decrease of microglia activation, neuronal damage and high antioxidant properties. The aim of this research was to evaluate the neuroprotective, antioxidant and anti-inflammatory activities of luteolin-7-O-glucoside (Lut7). Undifferentiated and retinoic acid (RA)-differentiated SH-SY5Y cells were pretreated with Lut7 and incubated with 6-hydroxydopamine (6-OHDA). Cytotoxic and neuroprotective effects were determined by MTT assay. Antioxidant capacity was determined by DPPH, FRAP, and ORAC assays. ROS production, mitochondrial membrane potential (ΔΨm), Caspase–3 activity, acetylcholinesterase inhibition (AChEI) and nuclear damage were also determined in SH-SY5Y cells. TNF-α, IL-6 and IL-10 release were evaluated in LPS-induced RAW264.7 cells by ELISA. In undifferentiated SH-SY5Y cells, Lut7 increased cell viability after 24 h, while in RA-differentiated SH-SY5Y cells, Lut7 increased cell viability after 24 and 48 h. Lut7 showed a high antioxidant activity when compared with synthetic antioxidants. In undifferentiated cells, Lut7 prevented mitochondrial membrane depolarization induced by 6-OHDA treatment, decreased Caspase-3 and AChE activity, and inhibited nuclear condensation and fragmentation. In LPS-stimulated RAW264.7 cells, Lut7 treatment reduced TNF-α levels and increased IL-10 levels after 3 and 24 h, respectively. In summary, the results suggest that Lut7 has neuroprotective effects, thus, further studies should be considered to validate its pharmacological potential in more complex models, aiming the treatment of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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20 pages, 3978 KiB  
Article
Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson’s Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon
by Ning Wang, Rui Li, Bainian Feng, Yuliang Cheng, Yahui Guo and He Qian
Int. J. Mol. Sci. 2022, 23(4), 2031; https://doi.org/10.3390/ijms23042031 - 12 Feb 2022
Cited by 10 | Viewed by 2471
Abstract
Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain–spleen and brain–gut axes in neurodegenerative diseases, including Parkinson’s disease (PD), and the immune response of the spleen [...] Read more.
Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain–spleen and brain–gut axes in neurodegenerative diseases, including Parkinson’s disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-β) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain–spleen and brain–gut axes in PD. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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21 pages, 3792 KiB  
Article
The Anxiolytic Drug Buspirone Prevents Rotenone-Induced Toxicity in a Mouse Model of Parkinson’s Disease
by Sarah Thomas Broome and Alessandro Castorina
Int. J. Mol. Sci. 2022, 23(3), 1845; https://doi.org/10.3390/ijms23031845 - 06 Feb 2022
Cited by 7 | Viewed by 3514
Abstract
A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson’s disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited [...] Read more.
A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson’s disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited neuroprotective activities, C57BL/6 mice were subjected to rotenone treatment (10mg/kg i.p for 21 days) to induce PD-like pathology and were co-treated with increasing dosages of buspirone (1, 3, or 10 mg/kg i.p.) to determine if the drug could prevent rotenone-induced damage to the central nervous system (CNS). We found that high dosages of buspirone prevented the behavioural deficits caused by rotenone in the open field test. Molecular and histological analyses confirmed that 10 mg/kg of buspirone prevented the degeneration of TH-positive neurons. Buspirone attenuated the induction of interleukin-1β and interleukin-6 expression by rotenone, and this was paralleled by the upregulation of arginase-1, brain-derived neurotrophic factor (BDNF), and activity-dependent neuroprotective protein (ADNP) in the midbrain, striatum, prefrontal cortex, amygdala, and hippocampus. Buspirone treatment also improved mitochondrial function and antioxidant activities. Lastly, the drug prevented the disruptions in the expression of two neuroprotective peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). These results pinpoint the neuroprotective efficacy of buspirone against rotenone toxicity, suggesting its potential use as a therapeutic agent in neurodegenerative and neuroinflammatory diseases, such as PD. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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17 pages, 3693 KiB  
Article
From Molecules to Behavior in Long-Term Inorganic Mercury Intoxication: Unraveling Proteomic Features in Cerebellar Neurodegeneration of Rats
by Leonardo Oliveira Bittencourt, Victória Santos Chemelo, Walessa Alana Bragança Aragão, Bruna Puty, Aline Dionizio, Francisco Bruno Teixeira, Mileni Silva Fernandes, Márcia Cristina Freitas Silva, Luanna Melo Pereira Fernandes, Edivaldo Herculano Corrêa de Oliveira, Marilia Afonso Rabelo Buzalaf, Maria Elena Crespo-Lopez, Cristiane do Socorro Ferraz Maia and Rafael Rodrigues Lima
Int. J. Mol. Sci. 2022, 23(1), 111; https://doi.org/10.3390/ijms23010111 - 22 Dec 2021
Cited by 12 | Viewed by 2938
Abstract
Mercury is a severe environmental pollutant with neurotoxic effects, especially when exposed for long periods. Although there are several evidences regarding mercury toxicity, little is known about inorganic mercury (IHg) species and cerebellum, one of the main targets of mercury associated with the [...] Read more.
Mercury is a severe environmental pollutant with neurotoxic effects, especially when exposed for long periods. Although there are several evidences regarding mercury toxicity, little is known about inorganic mercury (IHg) species and cerebellum, one of the main targets of mercury associated with the neurological symptomatology of mercurial poisoning. Besides that, the global proteomic profile assessment is a valuable tool to screen possible biomarkers and elucidate molecular targets of mercury neurotoxicity; however, the literature is still scarce. Thus, this study aimed to investigate the effects of long-term exposure to IHg in adult rats’ cerebellum and explore the modulation of the cerebellar proteome associated with biochemical and functional outcomes, providing evidence, in a translational perspective, of new mercury toxicity targets and possible biomarkers. Fifty-four adult rats were exposed to 0.375 mg/kg of HgCl2 or distilled water for 45 days using intragastric gavage. Then, the motor functions were evaluated by rotarod and inclined plane. The cerebellum was collected to quantify mercury levels, to assess the antioxidant activity against peroxyl radicals (ACAPs), the lipid peroxidation (LPO), the proteomic profile, the cell death nature by cytotoxicity and apoptosis, and the Purkinje cells density. The IHg exposure increased mercury levels in the cerebellum, reducing ACAP and increasing LPO. The proteomic approach revealed a total 419 proteins with different statuses of regulation, associated with different biological processes, such as synaptic signaling, energy metabolism and nervous system development, e.g., all these molecular changes are associated with increased cytotoxicity and apoptosis, with a neurodegenerative pattern on Purkinje cells layer and poor motor coordination and balance. In conclusion, all these findings feature a neurodegenerative process triggered by IHg in the cerebellum that culminated into motor functions deficits, which are associated with several molecular features and may be related to the clinical outcomes of people exposed to the toxicant. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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13 pages, 717 KiB  
Article
Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis
by Beata Dąbrowska-Bouta, Lidia Strużyńska, Marta Sidoryk-Węgrzynowicz and Grzegorz Sulkowski
Int. J. Mol. Sci. 2021, 22(21), 11330; https://doi.org/10.3390/ijms222111330 - 20 Oct 2021
Cited by 10 | Viewed by 1833
Abstract
Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. [...] Read more.
Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. The aim of the current study was to characterize the role of NMDA receptors in the induction of oxidative stress during the course of EAE. The effect of memantine, the uncompetitive NMDA receptor antagonist, on modulation of neurological deficits and oxidative stress in EAE rats was analyzed using several experimental approaches. We demonstrated that the expression of antioxidative enzymes (superoxide dismutases SOD1 and SOD2) were elevated in EAE rat brains. Under the same experimental conditions, we observed alterations in oxidative stress markers such as increased levels of malondialdehyde (MDA) and decreased levels of sulfhydryl (-SH) groups, both protein and non-protein (indicating protein damage), and a decline in reduced glutathione. Importantly, pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonist memantine improved the physical activity of EAE rats, alleviated neurological deficits such as paralysis of tail and hind limbs, and modulated oxidative stress parameters (MDA, -SH groups, SOD’s). Furthermore, the current therapy aiming to suppress NMDAR-induced oxidative stress was partially effective when NMDAR’s antagonist was administered at an early (asymptomatic) stage of EAE. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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Review

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38 pages, 2946 KiB  
Review
Targeting Fibronectin to Overcome Remyelination Failure in Multiple Sclerosis: The Need for Brain- and Lesion-Targeted Drug Delivery
by Pauline E. M. van Schaik, Inge S. Zuhorn and Wia Baron
Int. J. Mol. Sci. 2022, 23(15), 8418; https://doi.org/10.3390/ijms23158418 - 29 Jul 2022
Cited by 8 | Viewed by 3344
Abstract
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is [...] Read more.
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood–brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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21 pages, 10836 KiB  
Review
Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease
by José Ángel Martínez-Menárguez, Emma Martínez-Alonso, Mireia Cara-Esteban and Mónica Tomás
Int. J. Mol. Sci. 2021, 22(21), 12087; https://doi.org/10.3390/ijms222112087 - 08 Nov 2021
Cited by 9 | Viewed by 3215
Abstract
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause [...] Read more.
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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21 pages, 1479 KiB  
Review
Circulating miRNAs as Potential Biomarkers Distinguishing Relapsing–Remitting from Secondary Progressive Multiple Sclerosis. A Review
by Sylwia Pietrasik, Angela Dziedzic, Elzbieta Miller, Michal Starosta and Joanna Saluk-Bijak
Int. J. Mol. Sci. 2021, 22(21), 11887; https://doi.org/10.3390/ijms222111887 - 02 Nov 2021
Cited by 15 | Viewed by 2997
Abstract
Multiple sclerosis (MS) is a debilitating neurodegenerative, highly heterogeneous disease with a variable course. The most common MS subtype is relapsing–remitting (RR), having interchanging periods of worsening and relative stabilization. After a decade, in most RR patients, it alters into the secondary progressive [...] Read more.
Multiple sclerosis (MS) is a debilitating neurodegenerative, highly heterogeneous disease with a variable course. The most common MS subtype is relapsing–remitting (RR), having interchanging periods of worsening and relative stabilization. After a decade, in most RR patients, it alters into the secondary progressive (SP) phase, the most debilitating one with no clear remissions, leading to progressive disability deterioration. Among the greatest challenges for clinicians is understanding disease progression molecular mechanisms, since RR is mainly characterized by inflammatory processes, while in SP, the neurodegeneration prevails. This is especially important because distinguishing RR from the SP subtype early will enable faster implementation of appropriate treatment. Currently, the MS course is not well-correlated with the biomarkers routinely used in clinical practice. Despite many studies, there are still no reliable indicators correlating with the disease stage and its activity degree. Circulating microRNAs (miRNAs) may be considered valuable molecules for the MS diagnosis and, presumably, helpful in predicting disease subtype. MiRNA expression dysregulation is commonly observed in the MS course. Moreover, knowledge of diverse miRNA panel expression between RRMS and SPMS may allow for deterring disability progression through successful treatment. Therefore, in this review, we address the current state of research on differences in miRNA panel expression between the phases. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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27 pages, 1298 KiB  
Review
Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson’s Disease
by Gleyce Fonseca Cabral, Ana Paula Schaan, Giovanna C. Cavalcante, Camille Sena-dos-Santos, Tatiane Piedade de Souza, Natacha M. Souza Port’s, Jhully Azevedo dos Santos Pinheiro, Ândrea Ribeiro-dos-Santos and Amanda F. Vidal
Int. J. Mol. Sci. 2021, 22(18), 9839; https://doi.org/10.3390/ijms22189839 - 11 Sep 2021
Cited by 7 | Viewed by 3774
Abstract
Background: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the [...] Read more.
Background: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. Conclusions: Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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28 pages, 1564 KiB  
Review
From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy
by Yu-Jung Cheng, Chieh-Hsin Lin and Hsien-Yuan Lane
Int. J. Mol. Sci. 2021, 22(16), 8654; https://doi.org/10.3390/ijms22168654 - 11 Aug 2021
Cited by 23 | Viewed by 5152
Abstract
The impacts of menopause on neurodegenerative diseases, especially the changes in steroid hormones, have been well described in cell models, animal models, and humans. However, the therapeutic effects of hormone replacement therapy on postmenopausal women with neurodegenerative diseases remain controversial. The steroid hormones, [...] Read more.
The impacts of menopause on neurodegenerative diseases, especially the changes in steroid hormones, have been well described in cell models, animal models, and humans. However, the therapeutic effects of hormone replacement therapy on postmenopausal women with neurodegenerative diseases remain controversial. The steroid hormones, steroid hormone receptors, and downstream signal pathways in the brain change with aging and contribute to disease progression. Estrogen and progesterone are two steroid hormones which decline in circulation and the brain during menopause. Insulin-like growth factor 1 (IGF-1), which plays an import role in neuroprotection, is rapidly decreased in serum after menopause. Here, we summarize the actions of estrogen, progesterone, and IGF-1 and their signaling pathways in the brain. Since the incidence of Alzheimer’s disease (AD) is higher in women than in men, the associations of steroid hormone changes and AD are emphasized. The signaling pathways and cellular mechanisms for how steroid hormones and IGF-1 provide neuroprotection are also addressed. Finally, the molecular mechanisms of potential estrogen modulation on N-methyl-d-aspartic acid receptors (NMDARs) are also addressed. We provide the viewpoint of why hormone therapy has inconclusive results based on signaling pathways considering their complex response to aging and hormone treatments. Nonetheless, while diagnosable AD may not be treatable by hormone therapy, its preceding stage of mild cognitive impairment may very well be treatable by hormone therapy. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: From Molecular Basis to Therapy)
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