The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival

AbstractThe non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

Download Full-text

Angelica sinensis extract promotes neuronal survival by enhancing p38 MAPK–mediated hippocampal neurogenesis and dendritic growth in the chronic phase of transient global cerebral ischemia in rats

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114301 ◽

2021 ◽

pp. 114301

Author(s):

Chin-Yi Cheng ◽

Hui-Chi Huang ◽

Shung-Te Kao ◽

Yu-Chen Lee

Keyword(s):

Cerebral Ischemia ◽

P38 Mapk ◽

Dendritic Growth ◽

Neuronal Survival ◽

Chronic Phase ◽

Hippocampal Neurogenesis ◽

Global Cerebral Ischemia ◽

Angelica Sinensis ◽

Transient Global Cerebral Ischemia

Download Full-text

Stoichiometric Analysis of Shifting in Subcellular Compartmentalization of HSP70 within Ischemic Penumbra

Molecules ◽

10.3390/molecules26123578 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3578

Author(s):

Federica Mastroiacovo ◽

Francesca Biagioni ◽

Paola Lenzi ◽

Larisa Ryskalin ◽

Stefano Puglisi-Allegra ◽

...

Keyword(s):

Direct Evidence ◽

Neuronal Survival ◽

Hsp 70 ◽

Preclinical Models ◽

Brain Areas ◽

Cell Compartments ◽

Control Brain ◽

Disease Modifier ◽

Subcellular Compartmentalization

The heat shock protein (HSP) 70 is considered the main hallmark in preclinical studies to stain the peri-infarct region defined area penumbra in preclinical models of brain ischemia. This protein is also considered as a potential disease modifier, which may improve the outcome of ischemic damage. In fact, the molecule HSP70 acts as a chaperonine being able to impact at several level the homeostasis of neurons. Despite being used routinely to stain area penumbra in light microscopy, the subcellular placement of this protein within area penumbra neurons, to our knowledge, remains undefined. This is key mostly when considering studies aimed at deciphering the functional role of this protein as a determinant of neuronal survival. The general subcellular placement of HSP70 was grossly reported in studies using confocal microscopy, although no direct visualization of this molecule at electron microscopy was carried out. The present study aims to provide a direct evidence of HSP70 within various subcellular compartments. In detail, by using ultrastructural morphometry to quantify HSP70 stoichiometrically detected by immuno-gold within specific organelles we could compare the compartmentalization of the molecule within area penumbra compared with control brain areas. The study indicates that two cell compartments in control conditions own a high density of HSP70, cytosolic vacuoles and mitochondria. In these organelles, HSP70 is present in amount exceeding several-fold the presence in the cytosol. Remarkably, within area penumbra a loss of such a specific polarization is documented. This leads to the depletion of HSP70 from mitochondria and mostly cell vacuoles. Such an effect is expected to lead to significant variations in the ability of HSP70 to exert its physiological roles. The present findings, beyond defining the neuronal compartmentalization of HSP70 within area penumbra may lead to a better comprehension of its beneficial/detrimental role in promoting neuronal survival.

Download Full-text

Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

Science Advances ◽

10.1126/sciadv.abc1428 ◽

2020 ◽

Vol 6 (46) ◽

pp. eabc1428

Author(s):

A. Nakano-Kobayashi ◽

A. Fukumoto ◽

A. Morizane ◽

D. T. Nguyen ◽

T. M. Le ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Neuronal Survival ◽

Disease Model ◽

Neuronal Loss ◽

Induced Pluripotent Stem Cell ◽

Related Factor ◽

Induced Pluripotent ◽

Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

Download Full-text

LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

Cell Death and Differentiation ◽

10.1038/s41418-019-0422-6 ◽

2019 ◽

Vol 27 (4) ◽

pp. 1369-1382 ◽

Cited By ~ 4

Author(s):

Honglin Tan ◽

Mina Chen ◽

Dejiang Pang ◽

Xiaoqiang Xia ◽

Chongyangzi Du ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Neuronal Survival ◽

Disease Onset ◽

Alternative Mechanism ◽

Specific Expression ◽

Motor Neuron Survival ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

Download Full-text