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Protein Kinases and Neurodegenerative Diseases
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Protein Kinases and Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 33105

Special Issue Editors

Prof. Kohji Fukunaga

E-Mail Website
Guest Editor
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Interests: CaM kinase II; memory; intellectual disability; synaptic plasticity; neurodegeneration; amyloid beta; synuceluin; fatty acid binding protein
Dr. Ichiro Kawahata

E-Mail
Co-Guest Editor
Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Interests: CaMKII; neuropsychiatry disorders; drug addiction; neuroinflammation; dementia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein kinases have pivotal or detrimental functions in brain aging and neurodegenerative disorders. For example, PI3K/AKT/mTOR and AMPK pathways are essential for brain longevity through the regulation of protein synthesis and mitochondrial energy production, respectively. Mitogen-activated protein kinase pathways including JNK, p38, and ERK mediate neuronal damages via oxidative stress induced by brain ischemia and neurodegenerative disorders. Likewise, ASK-1/p38 signaling with CaMKII accounts for oxidative neuronal death. In addition, neuroinflammation and upregulation of death receptor family ligands such as TNFalpha promotes necrotic cell death, named necroptosis, which is mediated by receptor interacting protein kinase 1, RIPJ3, and mixed lineage kinase domain-like protein (MLKL). Apoptosis and necroptosis promote further cell death and neuroinflammation in neurodegenerative disorders including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. Our aim is to establish, with this Special Issue, a strong research network to share the pathological mechanisms mediated by protein kinases in human neurodegenerative disorders.

Prof. Dr. Kohji Fukunaga
Assoc. Prof. Ichiro Kawahata
Guest Editors

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Keywords

  • neurodegeneration
  • PI3K/AKT/mTOR pathway
  • AMPK
  • ASK-1/p38
  • CaMKII
  • PIPJ3

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Published Papers (6 papers)

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Editorial

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4 pages, 186 KiB  
Editorial
Protein Kinases and Neurodegenerative Diseases
by Ichiro Kawahata and Kohji Fukunaga
Int. J. Mol. Sci. 2023, 24(6), 5574; https://doi.org/10.3390/ijms24065574 - 14 Mar 2023
Cited by 10 | Viewed by 1919
Abstract
Global aging has led to an increase in age-related neurological disorders, which have become a societal problem [...] Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)

Research

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24 pages, 3023 KiB  
Article
Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction
by Eun-Joo Shin, Ji Hoon Jeong, Bao-Trong Nguyen, Naveen Sharma, Seung-Yeol Nah, Yoon Hee Chung, Yi Lee, Jae Kyung Byun, Toshitaka Nabeshima, Sung Kwon Ko and Hyoung-Chun Kim
Int. J. Mol. Sci. 2021, 22(13), 7219; https://doi.org/10.3390/ijms22137219 - 5 Jul 2021
Cited by 9 | Viewed by 3828
Abstract
It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng [...] Read more.
It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI. Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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17 pages, 3579 KiB  
Article
T-Type Ca2+ Enhancer SAK3 Activates CaMKII and Proteasome Activities in Lewy Body Dementia Mice Model
by Jing Xu, Ichiro Kawahata, Hisanao Izumi and Kohji Fukunaga
Int. J. Mol. Sci. 2021, 22(12), 6185; https://doi.org/10.3390/ijms22126185 - 8 Jun 2021
Cited by 8 | Viewed by 8516
Abstract
Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome system. More importantly, 26S proteasomal activity decreases in the brain of LBD patients. We recently introduced a T-type calcium channel [...] Read more.
Lewy bodies are pathological characteristics of Lewy body dementia (LBD) and are composed of α-synuclein (α-Syn), which is mostly degraded via the ubiquitin–proteasome system. More importantly, 26S proteasomal activity decreases in the brain of LBD patients. We recently introduced a T-type calcium channel enhancer SAK3 (ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)- 2H-spiro[cyclopentane-1,3-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate) for Alzheimer’s disease therapeutics. SAK3 enhanced the proteasome activity via CaMKII activation in amyloid precursor protein knock-in mice, promoting the degradation of amyloid-β plaques to improve cognition. At this point, we addressed whether SAK3 promotes the degradation of misfolded α-Syn and the aggregates in α-Syn preformed fibril (PFF)-injected mice. The mice were injected with α-Syn PFF in the dorsal striatum, and SAK3 (0.5 or 1.0 mg/kg) was administered orally for three months, either immediately or during the last month after injection. SAK3 significantly inhibited the accumulation of fibrilized phosphorylated-α-Syn in the substantia nigra. Accordingly, SAK3 significantly recovered mesencephalic dopamine neurons from cell death. Decreased α-Syn accumulation was closely associated with increased proteasome activity. Elevated CaMKII/Rpt-6 signaling possibly mediates the enhanced proteasome activity after SAK3 administration in the cortex and hippocampus. CaMKII/Rpt-6 activation also accounted for improved memory and cognition in α-Syn PFF-injected mice. These findings indicate that CaMKII/Rpt-6-dependent proteasomal activation by SAK3 recovers from α-Syn pathology in LBD. Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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26 pages, 2932 KiB  
Article
A Highly Selective In Vitro JNK3 Inhibitor, FMU200, Restores Mitochondrial Membrane Potential and Reduces Oxidative Stress and Apoptosis in SH-SY5Y Cells
by Stephanie Cristine Hepp Rehfeldt, Stefan Laufer and Márcia Inês Goettert
Int. J. Mol. Sci. 2021, 22(7), 3701; https://doi.org/10.3390/ijms22073701 - 2 Apr 2021
Cited by 44 | Viewed by 5982
Abstract
Current treatments for neurodegenerative diseases (ND) are symptomatic and do not affect disease progression. Slowing this progression remains a crucial unmet need for patients and their families. c-Jun N-terminal kinase 3 (JNK3) are related to several ND hallmarks including apoptosis, oxidative stress, excitotoxicity, [...] Read more.
Current treatments for neurodegenerative diseases (ND) are symptomatic and do not affect disease progression. Slowing this progression remains a crucial unmet need for patients and their families. c-Jun N-terminal kinase 3 (JNK3) are related to several ND hallmarks including apoptosis, oxidative stress, excitotoxicity, mitochondrial dysfunction, and neuroinflammation. JNK inhibitors can play an important role in addressing neuroprotection. This research aims to evaluate the neuroprotective, anti-inflammatory, and antioxidant effects of a synthetic compound (FMU200) with known JNK3 inhibitory activity in SH-SY5Y and RAW264.7 cell lines. SH-SY5Y cells were pretreated with FMU200 and cell damage was induced by 6-hydroxydopamine (6-OHDA) or hydrogen peroxide (H2O2). Cell viability and neuroprotective effect were assessed with an MTT assay. Flow cytometric analysis was performed to evaluate cell apoptosis. The H2O2-induced reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) were evaluated by DCFDA and JC-1 assays, respectively. The anti-inflammatory effect was determined in LPS-induced RAW264.7 cells by ELISA assay. In undifferentiated SH-SY5Y cells, FMU200 decreased neurotoxicity induced by 6-OHDA in approximately 20%. In RA-differentiated cells, FMU200 diminished cell death in approximately 40% and 90% after 24 and 48 h treatment, respectively. FMU200 reduced both early and late apoptotic cells, decreased ROS levels, restored mitochondrial membrane potential, and downregulated JNK phosphorylation after H2O2 exposure. In LPS-stimulated RAW264.7 cells, FMU200 reduced TNF-α levels after a 3 h treatment. FMU200 protects neuroblastoma SH-SY5Y cells against 6-OHDA- and H2O2-induced apoptosis, which may result from suppressing the JNK pathways. Our findings show that FMU200 can be a useful candidate for the treatment of neurodegenerative disorders. Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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Review

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14 pages, 2345 KiB  
Review
Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies
by Ichiro Kawahata, David I. Finkelstein and Kohji Fukunaga
Int. J. Mol. Sci. 2022, 23(11), 6216; https://doi.org/10.3390/ijms23116216 - 1 Jun 2022
Cited by 59 | Viewed by 6329
Abstract
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a [...] Read more.
α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson’s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson’s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy. Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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15 pages, 1910 KiB  
Review
Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)
by Raquel García-García, Laura Martín-Herrero, Laura Blanca-Pariente, Jesús Pérez-Cabello and Cintia Roodveldt
Int. J. Mol. Sci. 2021, 22(24), 13280; https://doi.org/10.3390/ijms222413280 - 10 Dec 2021
Cited by 9 | Viewed by 5113
Abstract
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3–5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying [...] Read more.
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3–5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling. Full article
(This article belongs to the Special Issue Protein Kinases and Neurodegenerative Diseases)
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