International Journal of Molecular Sciences

Editorial

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7 pages, 205 KiB

Open AccessEditorial

Neurodegenerative Disease: From Molecular Basis to Therapy

by Claudia Ricci

Int. J. Mol. Sci. 2024, 25(2), 967; https://doi.org/10.3390/ijms25020967 - 12 Jan 2024

Cited by 4 | Viewed by 3617

Abstract

Neurodegenerative diseases are a heterogeneous group of age-related disorders characterised by the progressive degeneration or death of neurons in the central or peripheral nervous system [...] Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

Research

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17 pages, 3013 KiB

Open AccessArticle

Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer’s Disease

by Hoau-Yan Wang, Erika Cecon, Julie Dam, Zhe Pei, Ralf Jockers and Lindsay H. Burns

Int. J. Mol. Sci. 2023, 24(18), 13927; https://doi.org/10.3390/ijms241813927 - 11 Sep 2023

Cited by 9 | Viewed by 6733

Abstract

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer’s disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA’s aberrant linkage to the α7 nicotinic [...] Read more.

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer’s disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA’s aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta_1–42 (Aβ₄₂)’s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam’s mechanism. We now show that simufilam reduced Aβ₄₂ binding to α7nAChR with a 10-picomolar IC₅₀ using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aβ₄₂ incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aβ₄₂-stimulated human astrocytes. In the AD transgenic mice, CCR5–G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA–CCR5 linkage and the CCR5–G protein coupling in these mice, while restoring CCR5′s responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA–receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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15 pages, 1736 KiB

Open AccessArticle

Repeated Methamphetamine Administration Results in Axon Loss Prior to Somatic Loss of Substantia Nigra Pars Compacta and Locus Coeruleus Neurons in Male but Not Female Mice

by Alexander Pilski and Steven M. Graves

Int. J. Mol. Sci. 2023, 24(17), 13039; https://doi.org/10.3390/ijms241713039 - 22 Aug 2023

Cited by 3 | Viewed by 1404

Abstract

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons [...] Read more.

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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14 pages, 8912 KiB

Open AccessArticle

The ε-Isozyme of Protein Kinase C (PKCε) Is Impaired in ALS Motor Cortex and Its Pulse Activation by Bryostatin-1 Produces Long Term Survival in Degenerating SOD1-G93A Motor Neuron-like Cells

by Valentina La Cognata, Agata Grazia D’Amico, Grazia Maugeri, Giovanna Morello, Maria Guarnaccia, Benedetta Magrì, Eleonora Aronica, Daniel L. Alkon, Velia D’Agata and Sebastiano Cavallaro

Int. J. Mol. Sci. 2023, 24(16), 12825; https://doi.org/10.3390/ijms241612825 - 15 Aug 2023

Cited by 2 | Viewed by 1917

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, characterized by a progressive depletion of upper and lower motor neurons (MNs) in the brain and spinal cord. The aberrant regulation of several PKC-mediated signal transduction pathways in ALS has been characterized so far, describing either impaired expression or altered activity of single PKC isozymes (α, β, ζ and δ). Here, we detailed the distribution and cellular localization of the ε-isozyme of protein kinase C (PKCε) in human postmortem motor cortex specimens and reported a significant decrease in both PKCε mRNA (PRKCE) and protein immunoreactivity in a subset of sporadic ALS patients. We furthermore investigated the steady-state levels of both pan and phosphorylated PKCε in doxycycline-activated NSC-34 cell lines carrying the human wild-type (WT) or mutant G93A SOD1 and the biological long-term effect of its transient agonism by Bryostatin-1. The G93A-SOD1 cells showed a significant reduction of the phosphoPKCε/panPKCε ratio compared to the WT. Moreover, a brief pulse activation of PKCε by Bryostatin-1 produced long-term survival in activated G93A-SOD1 degenerating cells in two different cell death paradigms (serum starvation and chemokines-induced toxicity). Altogether, the data support the implication of PKCε in ALS pathophysiology and suggests its pharmacological modulation as a potential neuroprotective strategy, at least in a subgroup of sporadic ALS patients. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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16 pages, 3002 KiB

Open AccessArticle

Molecular Changes in the Brain of the Wintering Calidris pusilla in the Mangroves of the Amazon River Estuary

by Patrick Douglas Corrêa Pereira, Ediely Pereira Henrique, Emanuel Ramos da Costa, Anderson de Jesus Falcão, Mauro André Damasceno de Melo, Maria Paula Cruz Schneider, Rommel Mario Rodriguez Burbano, Daniel Guerreiro Diniz, Nara Gyzely de Morais Magalhães, David Francis Sherry, Cristovam Wanderley Picanço Diniz and Cristovam Guerreiro-Diniz

Int. J. Mol. Sci. 2023, 24(16), 12712; https://doi.org/10.3390/ijms241612712 - 12 Aug 2023

Viewed by 2691

Abstract

Migrant birds prepare differently to fly north for breeding in the spring and for the flight to lower latitudes during autumn, avoiding the cold and food shortages of the Northern Hemisphere’s harsh winter. The molecular events associated with these fundamental stages in the [...] Read more.

Migrant birds prepare differently to fly north for breeding in the spring and for the flight to lower latitudes during autumn, avoiding the cold and food shortages of the Northern Hemisphere’s harsh winter. The molecular events associated with these fundamental stages in the life history of migrants include the differential gene expression in different tissues. Semipalmated sandpipers (Calidris pusilla) are Arctic-breeding shorebirds that migrate to the coast of South America during the non-breeding season. In a previous study, we demonstrated that between the beginning and the end of the wintering period, substantial glial changes and neurogenesis occur in the brain of C. pusilla. These changes follow the epic journey of the autumn migration when a 5-day non-stop transatlantic flight towards the coast of South America and the subsequent preparation for the long-distance flight of the spring migration takes place. Here, we tested the hypothesis that the differential gene expressions observed in the brains of individuals captured in the autumn and spring windows are consistent with the previously described cellular changes. We searched for differential gene expressions in the brain of the semipalmated sandpiper, of recently arrived birds (RA) from the autumnal migration, and that of individuals in the premigratory period (PM) in the spring. All individuals were collected in the tropical coastal of northern Brazil in the mangrove region of the Amazon River estuary. We generated a de novo neurotranscriptome for C. pusilla individuals and compared the gene expressions across libraries. To that end, we mapped an RNA-Seq that reads to the C. pusilla neurotranscriptome in four brain samples of each group and found that the differential gene expressions in newly arrived and premigratory birds were related with neurogenesis, metabolic pathways (ketone body biosynthetic and the catabolic and lipid biosynthetic processes), and glial changes (astrocyte-dopaminergic neuron signaling, astrocyte differentiation, astrocyte cell migration, and astrocyte activation involved in immune response), as well as genes related to the immune response to virus infections (Type I Interferons), inflammatory cytokines (IL-6, IL-1β, TNF, and NF-κB), NLRP3 inflammasome, anti-inflammatory cytokines (IL-10), and cell death pathways (pyroptosis- and caspase-related changes). Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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13 pages, 7516 KiB

Open AccessArticle

α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer’s Disease-like Pathology

by Nicole E. Eassa, Stephanie M. Perez, Angela M. Boley, Hannah B. Elam, Dishary Sharmin, James M. Cook and Daniel J. Lodge

Int. J. Mol. Sci. 2023, 24(14), 11788; https://doi.org/10.3390/ijms241411788 - 22 Jul 2023

Cited by 2 | Viewed by 1974

Abstract

Of the 35 million people in the world suffering from Alzheimer’s Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is [...] Read more.

Of the 35 million people in the world suffering from Alzheimer’s Disease (AD), up to half experience comorbid psychosis. Antipsychotics, used to treat psychosis, are contraindicated in elderly patients because they increase the risk of premature death. Reports indicate that the hippocampus is hyperactive in patients with psychosis and those with AD. Preclinical studies have demonstrated that the ventral hippocampus (vHipp) can regulate dopamine system function, which is thought to underlie symptoms of psychosis. A viral-mediated approach was used to express mutated human genes known to contribute to AD pathology: the Swedish (K670N, M671L), Florida (I716V), and London (V717I) mutations of amyloid precursor protein and two mutations (M146L and L286V) of presenilin 1 specifically in the vHipp, to investigate the selective contribution of AD-like pathology in this region. We observed a significant increase in dopamine neuron population activity and behavioral deficits in this AD-AAV model that mimics observations in rodent models with psychosis-like symptomatologies. Further, systemic administration of MP-III-022 (α5-GABAA receptor selective positive allosteric modulator) was able to reverse aberrant dopamine system function in AD-AAV rats. This study provides evidence for the development of drugs that target α5-GABAA receptors for patients with AD and comorbid psychosis. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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17 pages, 1483 KiB

Open AccessArticle

The QPLEX™ Plus Assay Kit for the Early Clinical Diagnosis of Alzheimer’s Disease

by Hunjong Na, Ki Young Shin, Dokyung Lee, Changsik Yoon, Sun-Ho Han, Jong-Chan Park, Inhee Mook-Jung, Jisung Jang and Sunghoon Kwon

Int. J. Mol. Sci. 2023, 24(13), 11119; https://doi.org/10.3390/ijms241311119 - 5 Jul 2023

Cited by 2 | Viewed by 1795

Abstract

We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-β1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer’s disease (AD) by correlating with cerebral amyloid [...] Read more.

We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-β1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer’s disease (AD) by correlating with cerebral amyloid deposition. Owing to the demand for early AD detection, we investigate the potential of our kit for the early clinical diagnosis of AD. A total of 1395 participants were recruited, and their blood samples were analyzed with the QPLEX™ kit. The average of QPLEX™ algorithm values in each group increased gradually in the order of the clinical progression continuum of AD: cognitively normal (0.382 ± 0.150), subjective cognitive decline (0.452 ± 0.130), mild cognitive impairment (0.484 ± 0.129), and AD (0.513 ± 0.136). The algorithm values between each group showed statistically significant differences among groups divided by Mini-Mental State Examination and Clinical Dementia Rating. The QPLEX™ algorithm values could be used to distinguish the clinical continuum of AD or cognitive function. Because blood-based diagnosis is more accessible, convenient, and cost- and time-effective than cerebral spinal fluid or positron emission tomography imaging-based diagnosis, the QPLEX™ kit can potentially be used for health checkups and the early clinical diagnosis of AD. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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16 pages, 3834 KiB

Open AccessArticle

LAR Downregulation Protects the Astrocytic U251 and Cocultured SH-SY5Y Cells in a Rotenone-Induced Parkinson’s Disease Cell Model

by Wei Zheng, Xiao Han, Bing Han, Gang Li, Jing Gan, Tian Wang, Bo Xu, Jie He, Wenxiao Du, Xiaolin Cao and Zhenhua Wang

Int. J. Mol. Sci. 2023, 24(13), 11111; https://doi.org/10.3390/ijms241311111 - 5 Jul 2023

Cited by 5 | Viewed by 2117

Abstract

Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of [...] Read more.

Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of LAR in a cell-based model of Parkinson’s disease (PD) in which U251 and SH-SY5Y cells were used as models of astrocytes and dopaminergic neurons, respectively. Cell viability, cell death, cell morphology, protein phosphorylation and expression, ATP levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were analyzed in the wild-type (WT) and heterozygous LAR-knockout astrocytoma U251 cells to assess the cell state, signal transduction, and mitochondrial function. LAR downregulation showed a protective effect in rotenone-exposed U251 cells by increasing cell viability, reducing cell mortality, and restoring appropriate cellular morphology. LAR downregulation enhanced IGF-1R phosphorylation and downstream signal transduction as evidenced by increases in the Akt and GSK-3β phosphorylation, as well as the upregulation of NRF2 and HO-1. The downregulation of LAR also augmented DJ-1 levels in these cells. The enhanced Akt and GSK-3β phosphorylation contributed to a reduced Bax/Bcl2 ratio and suppressed apoptosis after rotenone exposure. Heterozygous LAR-knockout U251 cells exhibited higher mitochondrial function evidenced by increased mitochondrial membrane potential, ATP contents, and reduced ROS production compared to the WT cells following rotenone exposure. Further studies showed that the astrocytic protection mediated by the heterozygous knockout of LAR was associated with the activation of Akt. A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3β phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone. Astrocytes provide structural and metabolic support to maintain neuronal health. Astrocytic glial cell-derived neurotrophic factor (GDNF) production is vital for dopaminergic neuron survival. Heterozygous LAR-knockout U251 cells produced higher amounts of GDNF than the WT cells. The SH-SY5Y cells cocultured with heterozygous LAR-knockout U251 cells exhibited greater viability than that of cells cocultured with WT U251 cells in response to rotenone. Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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17 pages, 4923 KiB

Open AccessArticle

ARL6IP5 Ameliorates α-Synuclein Burden by Inducing Autophagy via Preventing Ubiquitination and Degradation of ATG12

by Ibrar Siddique, Kajal Kamble, Sakshi Gupta, Kavita Solanki, Sumnil Bhola, Nuzhat Ahsan and Sarika Gupta

Int. J. Mol. Sci. 2023, 24(13), 10499; https://doi.org/10.3390/ijms241310499 - 22 Jun 2023

Cited by 9 | Viewed by 1977

Abstract

Recent advanced studies in neurodegenerative diseases have revealed several links connecting autophagy and neurodegeneration. Autophagy is the major cellular degradation process for the removal of toxic protein aggregates responsible for neurodegenerative diseases. More than 30 autophagy-related proteins have been identified as directly participating [...] Read more.

Recent advanced studies in neurodegenerative diseases have revealed several links connecting autophagy and neurodegeneration. Autophagy is the major cellular degradation process for the removal of toxic protein aggregates responsible for neurodegenerative diseases. More than 30 autophagy-related proteins have been identified as directly participating in the autophagy process. Proteins regulating the process of autophagy are much more numerous and unknown. To address this, in our present study, we identified a novel regulator (ARL6IP5) of neuronal autophagy and showed that the level of ARL6IP5 decreases in the brain with age and in Parkinson’s disease in mice and humans. Moreover, a cellular model of PD (Wild type and A53T mutant α-synuclein overexpression) has also shown decreased levels of ARL6IP5. ARL6IP5 overexpression reduces α-synuclein aggregate burden and improves cell survival in an A53T model of Parkinson’s disease. Interestingly, detailed mechanistic studies revealed that ARL6IP5 is an autophagy inducer. ARL6IP5 enhances Rab1-dependent autophagosome initiation and elongation by stabilizing free ATG12. We report for the first time that α-synuclein downregulates ARL6IP5 to inhibit autophagy-dependent clearance of toxic aggregates that exacerbate neurodegeneration. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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16 pages, 2718 KiB

Open AccessArticle

Neuroprotection of Andrographolide against Neurotoxin MPP⁺-Induced Apoptosis in SH-SY5Y Cells via Activating Mitophagy, Autophagy, and Antioxidant Activities

by Prachayaporn Prasertsuksri, Pichnaree Kraokaew, Kanta Pranweerapaiboon, Prasert Sobhon and Kulathida Chaithirayanon

Int. J. Mol. Sci. 2023, 24(10), 8528; https://doi.org/10.3390/ijms24108528 - 10 May 2023

Cited by 11 | Viewed by 3800

Abstract

Parkinson’s disease (PD) is associated with dopaminergic neuron loss and alpha-synuclein aggregation caused by ROS overproduction, leading to mitochondrial dysfunction and autophagy impairment. Recently, andrographolide (Andro) has been extensively studied for various pharmacological properties, such as anti-diabetic, anti-cancer, anti-inflammatory, and anti-atherosclerosis. However, its [...] Read more.

Parkinson’s disease (PD) is associated with dopaminergic neuron loss and alpha-synuclein aggregation caused by ROS overproduction, leading to mitochondrial dysfunction and autophagy impairment. Recently, andrographolide (Andro) has been extensively studied for various pharmacological properties, such as anti-diabetic, anti-cancer, anti-inflammatory, and anti-atherosclerosis. However, its potential neuroprotective effects on neurotoxin MPP⁺-induced SH-SY5Y cells, a cellular PD model, remain uninvestigated. In this study, we hypothesized that Andro has neuroprotective effects against MPP⁺-induced apoptosis, which may be mediated through the clearance of dysfunctional mitochondria by mitophagy and ROS by antioxidant activities. Herein, Andro pretreatment could attenuate MPP⁺-induced neuronal cell death that was reflected by reducing mitochondrial membrane potential (MMP) depolarization, alpha-synuclein, and pro-apoptotic proteins expressions. Concomitantly, Andro attenuated MPP⁺-induced oxidative stress through mitophagy, as indicated by increasing colocalization of MitoTracker Red with LC3, upregulations of the PINK1–Parkin pathway, and autophagy-related proteins. On the contrary, Andro-activated autophagy was compromised when pretreated with 3-MA. Furthermore, Andro activated the Nrf2/KEAP1 pathway, leading to increasing genes encoding antioxidant enzymes and activities. This study elucidated that Andro exhibited significant neuroprotective effects against MPP⁺-induced SH-SY5Y cell death in vitro by enhancing mitophagy and clearance of alpha-synuclein through autophagy, as well as increasing antioxidant capacity. Our results provide evidence that Andro could be considered a potential supplement for PD prevention. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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13 pages, 1617 KiB

Open AccessArticle

NAADP-Evoked Ca²⁺ Signaling Leads to Mutant Huntingtin Aggregation and Autophagy Impairment in Murine Astrocytes

by Cássia Arruda de Souza Pereira, Natalia de Castro Medaglia, Rodrigo Portes Ureshino, Claudia Bincoletto, Manuela Antonioli, Gian Maria Fimia, Mauro Piacentini, Gustavo José da Silva Pereira, Adolfo Garcia Erustes and Soraya Soubhi Smaili

Int. J. Mol. Sci. 2023, 24(6), 5593; https://doi.org/10.3390/ijms24065593 - 15 Mar 2023

Cited by 9 | Viewed by 2185

Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by mutations in the huntingtin gene (mHtt), causing an unstable repeat of the CAG trinucleotide, leading to abnormal long repeats of polyglutamine (poly-Q) in the N-terminal region of the huntingtin, which form abnormal conformations [...] Read more.

Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by mutations in the huntingtin gene (mHtt), causing an unstable repeat of the CAG trinucleotide, leading to abnormal long repeats of polyglutamine (poly-Q) in the N-terminal region of the huntingtin, which form abnormal conformations and aggregates. Alterations in Ca²⁺ signaling are involved in HD models and the accumulation of mutated huntingtin interferes with Ca²⁺ homeostasis. Lysosomes are intracellular Ca²⁺ storages that participate in endocytic and lysosomal degradation processes, including autophagy. Nicotinic acid adenine dinucleotide phosphate (NAADP) is an intracellular second messenger that promotes Ca²⁺ release from the endo-lysosomal system via Two-Pore Channels (TPCs) activation. Herein, we show the impact of lysosomal Ca²⁺ signals on mHtt aggregation and autophagy blockade in murine astrocytes overexpressing mHtt-Q74. We observed that mHtt-Q74 overexpression causes an increase in NAADP-evoked Ca²⁺ signals and mHtt aggregation, which was inhibited in the presence of Ned-19, a TPC antagonist, or BAPTA-AM, a Ca²⁺ chelator. Additionally, TPC2 silencing revert the mHtt aggregation. Furthermore, mHtt has been shown co-localized with TPC2 which may contribute to its effects on lysosomal homeostasis. Moreover, NAADP-mediated autophagy was also blocked since its function is dependent on lysosomal functionality. Taken together, our data show that increased levels of cytosolic Ca²⁺ mediated by NAADP causes mHtt aggregation. Additionally, mHtt co-localizes with the lysosomes, where it possibly affects organelle functions and impairs autophagy. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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25 pages, 2336 KiB

Open AccessArticle

Adaptive Stimulations in a Biophysical Network Model of Parkinson’s Disease

by Thomas Stojsavljevic, Yixin Guo and Dominick Macaluso

Int. J. Mol. Sci. 2023, 24(6), 5555; https://doi.org/10.3390/ijms24065555 - 14 Mar 2023

Cited by 1 | Viewed by 1934

Abstract

Deep brain stimulation (DBS)—through a surgically implanted electrode to the subthalamic nucleus (STN)—has become a widely used therapeutic option for the treatment of Parkinson’s disease and other neurological disorders. The standard conventional high-frequency stimulation (HF) that is currently used has several drawbacks. To [...] Read more.

Deep brain stimulation (DBS)—through a surgically implanted electrode to the subthalamic nucleus (STN)—has become a widely used therapeutic option for the treatment of Parkinson’s disease and other neurological disorders. The standard conventional high-frequency stimulation (HF) that is currently used has several drawbacks. To overcome the limitations of HF, researchers have been developing closed-loop and demand-controlled, adaptive stimulation protocols wherein the amount of current that is delivered is turned on and off in real-time in accordance with a biophysical signal. Computational modeling of DBS in neural network models is an increasingly important tool in the development of new protocols that aid researchers in animal and clinical studies. In this computational study, we seek to implement a novel technique of DBS where we stimulate the STN in an adaptive fashion using the interspike time of the neurons to control stimulation. Our results show that our protocol eliminates bursts in the synchronized bursting neuronal activity of the STN, which is hypothesized to cause the failure of thalamocortical neurons (TC) to respond properly to excitatory cortical inputs. Further, we are able to significantly decrease the TC relay errors, representing potential therapeutics for Parkinson’s disease. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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16 pages, 3757 KiB

Open AccessArticle

Origin of Elevated S-Glutathionylated GAPDH in Chronic Neurodegenerative Diseases

by Paul A. Hyslop, Leonard N. Boggs and Michael O. Chaney

Int. J. Mol. Sci. 2023, 24(6), 5529; https://doi.org/10.3390/ijms24065529 - 14 Mar 2023

Cited by 4 | Viewed by 1825

Abstract

H₂O₂-oxidized glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalytic cysteine residues (C_c(SH) undergo rapid S-glutathionylation. Restoration of the enzyme activity is accomplished by thiol/disulfide S_N2 displacement (directly or enzymatically) forming glutathione disulfide (G(SS)G) and active enzyme, a process that [...] Read more.

H₂O₂-oxidized glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalytic cysteine residues (C_c(SH) undergo rapid S-glutathionylation. Restoration of the enzyme activity is accomplished by thiol/disulfide S_N2 displacement (directly or enzymatically) forming glutathione disulfide (G(SS)G) and active enzyme, a process that should be facile as C_c(SH) reside on the subunit surface. As S-glutathionylated GAPDH accumulates following ischemic and/or oxidative stress, in vitro/silico approaches have been employed to address this paradox. C_c(SH) residues were selectively oxidized and S-glutathionylated. Kinetics of GAPDH dehydrogenase recovery demonstrated that glutathione is an ineffective reactivator of S-glutathionylated GAPDH compared to dithiothreitol. Molecular dynamic simulations (MDS) demonstrated strong binding interactions between local residues and S-glutathione. A second glutathione was accommodated for thiol/disulfide exchange forming a tightly bound glutathione disulfide G(SS)G. The proximal sulfur centers of G(SS)G and C_c(SH) remained within covalent bonding distance for thiol/disulfide exchange resonance. Both these factors predict inhibition of dissociation of G(SS)G, which was verified by biochemical analysis. MDS also revealed that both S-glutathionylation and bound G(SS)G significantly perturbed subunit secondary structure particularly within the S-loop, region which interacts with other cellular proteins and mediates NAD(P)⁺ binding specificity. Our data provides a molecular rationale for how oxidative stress elevates S-glutathionylated GAPDH in neurodegenerative diseases and implicates novel targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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Review

Jump to: Editorial, Research, Other

17 pages, 1150 KiB

Open AccessReview

Amyloid Precursor Protein and Alzheimer’s Disease

by Kseniia S. Orobets and Andrey L. Karamyshev

Int. J. Mol. Sci. 2023, 24(19), 14794; https://doi.org/10.3390/ijms241914794 - 30 Sep 2023

Cited by 16 | Viewed by 5112

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders associated with age or inherited mutations. It is characterized by severe dementia in the late stages that affect memory, cognitive functions, and daily life overall. AD progression is linked to the accumulation [...] Read more.

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders associated with age or inherited mutations. It is characterized by severe dementia in the late stages that affect memory, cognitive functions, and daily life overall. AD progression is linked to the accumulation of cytotoxic amyloid beta (Aβ) and hyperphosphorylated tau protein combined with other pathological features such as synaptic loss, defective energy metabolism, imbalances in protein, and metal homeostasis. Several treatment options for AD are under investigation, including antibody-based therapy and stem cell transplantation. Amyloid precursor protein (APP) is a membrane protein considered to play a main role in AD pathology. It is known that APP in physiological conditions follows a non-amyloidogenic pathway; however, it can proceed to an amyloidogenic scenario, which leads to the generation of extracellular deleterious Aβ plaques. Not all steps of APP biogenesis are clear so far, and these questions should be addressed in future studies. AD is a complex chronic disease with many factors that contribute to disease progression. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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16 pages, 1312 KiB

Open AccessReview

Vitamin E and Its Molecular Effects in Experimental Models of Neurodegenerative Diseases

by Bianca Caroline da Cunha Germano, Lara Cristina Carlos de Morais, Francisca Idalina Neta, Amélia Carolina Lopes Fernandes, Francisco Irochima Pinheiro, Amália Cinthia Meneses do Rego, Irami Araújo Filho, Eduardo Pereira de Azevedo, José Rodolfo Lopes de Paiva Cavalcanti, Fausto Pierdona Guzen and Ricardo Ney Cobucci

Int. J. Mol. Sci. 2023, 24(13), 11191; https://doi.org/10.3390/ijms241311191 - 7 Jul 2023

Cited by 18 | Viewed by 3943

Abstract

With the advancement of in vivo studies and clinical trials, the pathogenesis of neurodegenerative diseases has been better understood. However, gaps still need to be better elucidated, which justifies the publication of reviews that explore the mechanisms related to the development of these [...] Read more.

With the advancement of in vivo studies and clinical trials, the pathogenesis of neurodegenerative diseases has been better understood. However, gaps still need to be better elucidated, which justifies the publication of reviews that explore the mechanisms related to the development of these diseases. Studies show that vitamin E supplementation can protect neurons from the damage caused by oxidative stress, with a positive impact on the prevention and progression of neurodegenerative diseases. Thus, this review aims to summarize the scientific evidence of the effects of vitamin E supplementation on neuroprotection and on neurodegeneration markers in experimental models. A search for studies published between 2000 and 2023 was carried out in the PubMed, Web of Science, Virtual Health Library (BVS), and Embase databases, in which the effects of vitamin E in experimental models of neurodegeneration were investigated. A total of 5669 potentially eligible studies were identified. After excluding the duplicates, 5373 remained, of which 5253 were excluded after checking the titles, 90 articles after reading the abstracts, and 11 after fully reviewing the manuscripts, leaving 19 publications to be included in this review. Experiments with in vivo models of neurodegenerative diseases demonstrated that vitamin E supplementation significantly improved memory, cognition, learning, motor function, and brain markers associated with neuroregeneration and neuroprotection. Vitamin E supplementation reduced beta-amyloid (Aβ) deposition and toxicity in experimental models of Alzheimer’s disease. In addition, it decreased tau-protein hyperphosphorylation and increased superoxide dismutase and brain-derived neurotrophic factor (BDNF) levels in rodents, which seems to indicate the potential use of vitamin E in preventing and delaying the progress of degenerative lesions in the central nervous system. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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14 pages, 1263 KiB

Open AccessReview

Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination

by Jun-Hao Wen, Xiang-Hong He, Ze-Sen Feng, Dong-Yi Li, Ji-Xin Tang and Hua-Feng Liu

Int. J. Mol. Sci. 2023, 24(10), 8593; https://doi.org/10.3390/ijms24108593 - 11 May 2023

Cited by 24 | Viewed by 6168

Abstract

The accumulation of protein aggregates is the hallmark of many neurodegenerative diseases. The dysregulation of protein homeostasis (or proteostasis) caused by acute proteotoxic stresses or chronic expression of mutant proteins can lead to protein aggregation. Protein aggregates can interfere with a variety of [...] Read more.

The accumulation of protein aggregates is the hallmark of many neurodegenerative diseases. The dysregulation of protein homeostasis (or proteostasis) caused by acute proteotoxic stresses or chronic expression of mutant proteins can lead to protein aggregation. Protein aggregates can interfere with a variety of cellular biological processes and consume factors essential for maintaining proteostasis, leading to a further imbalance of proteostasis and further accumulation of protein aggregates, creating a vicious cycle that ultimately leads to aging and the progression of age-related neurodegenerative diseases. Over the long course of evolution, eukaryotic cells have evolved a variety of mechanisms to rescue or eliminate aggregated proteins. Here, we will briefly review the composition and causes of protein aggregation in mammalian cells, systematically summarize the role of protein aggregates in the organisms, and further highlight some of the clearance mechanisms of protein aggregates. Finally, we will discuss potential therapeutic strategies that target protein aggregates in the treatment of aging and age-related neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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20 pages, 1249 KiB

Open AccessReview

Appropriate Macronutrients or Mineral Elements Are Beneficial to Improve Depression and Reduce the Risk of Depression

by Zhengyang Quan, Hui Li, Zhenzhen Quan and Hong Qing

Int. J. Mol. Sci. 2023, 24(8), 7098; https://doi.org/10.3390/ijms24087098 - 12 Apr 2023

Cited by 10 | Viewed by 4527

Abstract

Depression is a common mental disorder that seriously affects the quality of life and leads to an increasing global suicide rate. Macro, micro, and trace elements are the main components that maintain normal physiological functions of the brain. Depression is manifested in abnormal [...] Read more.

Depression is a common mental disorder that seriously affects the quality of life and leads to an increasing global suicide rate. Macro, micro, and trace elements are the main components that maintain normal physiological functions of the brain. Depression is manifested in abnormal brain functions, which are considered to be tightly related to the imbalance of elements. Elements associated with depression include glucose, fatty acids, amino acids, and mineral elements such as lithium, zinc, magnesium, copper, iron, and selenium. To explore the relationship between these elements and depression, the main literature in the last decade was mainly searched and summarized on PubMed, Google Scholar, Scopus, Web of Science, and other electronic databases with the keywords “depression, sugar, fat, protein, lithium, zinc, magnesium, copper, iron, and selenium”. These elements aggravate or alleviate depression by regulating a series of physiological processes, including the transmission of neural signals, inflammation, oxidative stress, neurogenesis, and synaptic plasticity, which thus affect the expression or activity of physiological components such as neurotransmitters, neurotrophic factors, receptors, cytokines, and ion-binding proteins in the body. For example, excessive fat intake can lead to depression, with possible mechanisms including inflammation, increased oxidative stress, reduced synaptic plasticity, and decreased expression of 5-Hydroxytryptamine (5-HT), Brain Derived Neurotrophic Factor (BDNF), Postsynaptic density protein 95(PSD-95), etc. Supplementing mineral elements, such as selenium, zinc, magnesium, or lithium as a psychotropic medication is mostly used as an auxiliary method to improve depression with other antidepressants. In general, appropriate nutritional elements are essential to treat depression and prevent the risk of depression. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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23 pages, 1009 KiB

Open AccessReview

New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

by Botond Penke, Mária Szűcs and Ferenc Bogár

Int. J. Mol. Sci. 2023, 24(6), 5383; https://doi.org/10.3390/ijms24065383 - 11 Mar 2023

Cited by 17 | Viewed by 6938

Abstract

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive [...] Read more.

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60–80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: β-amyloid (Aβ) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aβ and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aβ and pTau aggregates has been an old drug target. Recently, successful Aβ clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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67 pages, 6516 KiB

Open AccessPerspective

The Amyloid Cascade Hypothesis 2.0 for Alzheimer’s Disease and Aging-Associated Cognitive Decline: From Molecular Basis to Effective Therapy

by Vladimir Volloch and Sophia Rits-Volloch

Int. J. Mol. Sci. 2023, 24(15), 12246; https://doi.org/10.3390/ijms241512246 - 31 Jul 2023

Cited by 13 | Viewed by 1778

Abstract

With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer’s disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the [...] Read more.

With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer’s disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-β (Aβ) in the disease, necessitated by the observation that all AD-causing mutations affect, in one way or another, Aβ. Yet, even this narrow commonality is superficial since AD-causing Aβ of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular Aβ, in the latter, it is triggered by Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ) and driven by iAβ generated independently of AβPP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of AβPP-derived iAβ, which occurs via internalization of secreted Aβ and through intracellular retention of a fraction of Aβ produced by AβPP proteolysis. When AβPP-derived iAβ reaches critical levels, it activates a self-perpetuating AβPP-independent production of iAβ that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of iAβ accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in AβPP-independent generation of iAβ, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic AβPP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of AβPP-derived iAβ can be effective only protectively for AD, the targeted degradation of iAβ is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential iAβ-degrading drugs. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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10 pages, 1732 KiB

Open AccessConcept Paper

Obstetric Neuropathy in Diabetic Patients: The “Double Hit Hypothesis”

by Dieu Thao Nguyen, Mohammad Hooshmand Zaferanieh, Asa C. Black, Jr., Kamron Reza Hamedi, Richard L. Goodwin and Thomas I. Nathaniel

Int. J. Mol. Sci. 2023, 24(7), 6812; https://doi.org/10.3390/ijms24076812 - 6 Apr 2023

Cited by 2 | Viewed by 2148

Abstract

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our [...] Read more.

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the “first hit” hypothesis. The delivery process itself—the “second hit”—can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both “hits” pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy)

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