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Brain Diseases: on Signaling Pathways and Miswired Networks
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Brain Diseases: on Signaling Pathways and Miswired Networks

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 (30 April 2021) | Viewed by 12382

Special Issue Editor

Dr. Tam Thanh Quach

E-Mail Website
Guest Editor
Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA
Interests: gene transfer/therapy; transgenic mice; hippocampus rejuvenation; brain disorders; intellectual ability and disability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The purpose of this Special Issue entitled “Brain Diseases: on Signaling Pathways and Miswired Networks” is to discuss some of the recent advances in the use of genetic technology in the discovery of different interplayed/novel signaling pathways implicated in the altered neuronal networks involved in the pathogenesis of intellectual disabilities (IDs: Down/Rett/ Fragile X or DiGeorge syndrome) and various neurodegenerative diseases (NDs: Alzheimer’s/Parkinson’s/Huntington’s/Creutzfeldt–Jacob/Pick/ALS disorders), but not limited to these. Although pathologically, both ID and ND are deficits of neuronal network connectivity caused by signaling/genetic factors and both have presented common altered neuronal network structures, NDs are considered as ageing-associated disorders and are attributed to the accumulation/aggregation of pathogenic proteins while IDs are neurodevelopmental disorders associated with gene mutations/chromosome deletions/rearrangements that can be diagnosed in children aged 0 to 5 years. On the other hand, the sequencing of human genome identified ~30,000 genes, suggesting that the complex functional phenotype of an individual is not only directly related to the number of coding candidate genes but also on the genomic/proteomic-interactomic networks, the epigenetic factors, and the non-linear crosstalk between them. Consequently, it is important to highlight the interaction between different molecular levels and how this contributes to the functional diversity in different time periods, from birth to ageing. Finally, because of the scarcity of post-mortem brain patients and the important ethical regulation, we would also cover studies with transgenic animal models. They frequently make it possible to identify a single gene (dys)function, and help to decipher/explore the detailed genetic processes underlying disease pathogenesis or to rescue abnormalities through experimental gene transfer.

This Special Issue welcomes review/original manuscripts highlighting the molecular mechanisms and/or the multi-omics analyses of genetic-rejuvenation/-protection/-treatments of ID/ND using in vitro cultured cells, in vivo animal models, and in clinical settings. These approaches may provide novel/good references for future network studies and treatment as well.

Dr. Tam Thanh Quach
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegenerative/neurodevelopment disorders
  • neuronal networks
  • rejuvenation
  • transgenic animals
  • gene identification/transfer/therapy
  • chromosomal rearrangement/deletion
  • cognitive deficit

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Published Papers (3 papers)

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Research

21 pages, 10819 KiB  
Article
n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway
by Jui-Hao Lee, Si-Yin Lin, Jen-Wei Liu, Shinn-Zong Lin, Horng-Jyh Harn and Tzyy-Wen Chiou
Int. J. Mol. Sci. 2021, 22(12), 6339; https://doi.org/10.3390/ijms22126339 - 13 Jun 2021
Cited by 15 | Viewed by 3381
Abstract
Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading [...] Read more.
Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3. Full article
(This article belongs to the Special Issue Brain Diseases: on Signaling Pathways and Miswired Networks)
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19 pages, 3158 KiB  
Communication
Impaired Expression of GABA Signaling Components in the Alzheimer’s Disease Middle Temporal Gyrus
by Karan Govindpani, Clinton Turner, Henry J. Waldvogel, Richard L. M. Faull and Andrea Kwakowsky
Int. J. Mol. Sci. 2020, 21(22), 8704; https://doi.org/10.3390/ijms21228704 - 18 Nov 2020
Cited by 47 | Viewed by 3979
Abstract
γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter, playing a central role in the regulation of cortical excitability and the maintenance of the excitatory/inhibitory (E/I) balance. Several lines of evidence point to a remodeling of the cerebral GABAergic system in Alzheimer’s disease (AD), [...] Read more.
γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter, playing a central role in the regulation of cortical excitability and the maintenance of the excitatory/inhibitory (E/I) balance. Several lines of evidence point to a remodeling of the cerebral GABAergic system in Alzheimer’s disease (AD), with past studies demonstrating alterations in GABA receptor and transporter expression, GABA synthesizing enzyme activity and focal GABA concentrations in post-mortem tissue. AD is a chronic neurodegenerative disorder with a poorly understood etiology and the temporal cortex is one of the earliest regions in the brain to be affected by AD neurodegeneration. Utilizing NanoString nCounter analysis, we demonstrate here the transcriptional downregulation of several GABA signaling components in the post-mortem human middle temporal gyrus (MTG) in AD, including the GABAA receptor α1, α2, α3, α5, β1, β2, β3, δ, γ2, γ3, and θ subunits and the GABAB receptor 2 (GABABR2) subunit. In addition to this, we note the transcriptional upregulation of the betaine-GABA transporter (BGT1) and GABA transporter 2 (GAT2), and the downregulation of the 67 kDa isoform of glutamate decarboxylase (GAD67), the primary GABA synthesizing enzyme. The functional consequences of these changes require further investigation, but such alterations may underlie disruptions to the E/I balance that are believed to contribute to cognitive decline in AD. Full article
(This article belongs to the Special Issue Brain Diseases: on Signaling Pathways and Miswired Networks)
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21 pages, 7760 KiB  
Article
Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains
by Angéla Kecskés, Krisztina Pohóczky, Miklós Kecskés, Zoltán V. Varga, Viktória Kormos, Éva Szőke, Nóra Henn-Mike, Máté Fehér, József Kun, Attila Gyenesei, Éva Renner, Miklós Palkovits, Péter Ferdinandy, István M. Ábrahám, Balázs Gaszner and Zsuzsanna Helyes
Int. J. Mol. Sci. 2020, 21(20), 7788; https://doi.org/10.3390/ijms21207788 - 21 Oct 2020
Cited by 24 | Viewed by 4079
Abstract
Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, [...] Read more.
Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates. Full article
(This article belongs to the Special Issue Brain Diseases: on Signaling Pathways and Miswired Networks)
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