Faculty Opinions recommendation of Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo.

Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid–induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.

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Rab7 Reduces α-Synuclein Toxicity in Rats and Primary Neurons

10.21203/rs.3.rs-277472/v1 ◽

2021 ◽

Author(s):

Éva M. Szegõ ◽

Eva M. Szegö ◽

Chris Van den Haute ◽

Lennart Höfs ◽

Veerle Baekelandt ◽

...

Keyword(s):

Dna Damage ◽

Rat Brain ◽

Neuronal Degeneration ◽

Degradation Pathway ◽

Alpha Synuclein ◽

Dominant Negative ◽

Primary Neurons ◽

Vicious Cycle ◽

Axon Terminals

Abstract BackgroundDuring the pathogenesis of Parkinson’s disease (PD), aggregation of alpha-synuclein (αSyn) induces a vicious cycle of cellular impairments that lead to neurodegeneration. Consequently, removing toxic αSyn aggregates constitutes a plausible strategy against PD. In this work, we tested whether stimulating the autolysosomal degradation of αSyn aggregates through the Ras-related in brain 7 (Rab7) pathway can reverse αSyn-induced cellular impairment and prevent neurodegeneration in vivo.MethodsThe disease-related A53T mutant of αSyn was expressed in primary neurons and in dopaminergic neurons of the rat brain simultaneously with wild type (WT) Rab7 or its dominant-negative T22N mutant as a control. The cellular integrity was quantified by morphological and biochemical analyses.ResultsIn primary neurons, WT Rab7 rescued the αSyn -induced loss of neurons and neurites. Furthermore, Rab7 decreased the amount of reactive oxygen species and the amount of Triton X-100 insoluble αSyn. In rat brain, WT Rab7 reduced αSyn -induced loss of dopaminergic axon terminals in the striatum and the loss of dopaminergic dendrites in the substantia nigra pars reticulata. Further, WT Rab7 lowered αSyn pathology as quantified by phosphorylated αSyn staining. Finally, WT Rab7 attenuated αSyn-induced DNA damage in primary neurons and rat brain.ConclusionRab7 reduced αSyn-induced pathology, ameliorated αSyn-induced neuronal degeneration, oxidative stress and DNA damage. These findings indicate that Rab7 is able to disrupt the vicious cycle of cellular impairment, αSyn pathology and neurodegeneration present in PD. Stimulation of Rab7 and the autolysosomal degradation pathway could therefore constitute a beneficial strategy for PD.

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In vivo evaluation of ziram induced acute toxicity on pathomorphology of broiler chicken

Journal of Applied and Natural Science ◽

10.31018/jans.v8i4.1113 ◽

2016 ◽

Vol 8 (4) ◽

pp. 2206-2211

Author(s):

Majid Shafi ◽

Shayaib A. Kamil ◽

Masood S. Mir ◽

S. Adil ◽

Showkat A. Shah ◽

...

Keyword(s):

Broiler Chicken ◽

Neuronal Degeneration ◽

Histopathological Examination ◽

Lymphoid Cells ◽

Bursa Of Fabricius ◽

Poultry Feed ◽

In Vivo Evaluation ◽

Vascular Congestion ◽

Gross Examination

Fungicides are usually used in agriculture and often find their way in poultry feed. Therefore, a study was undertaken to study the in vivo effect of one such fungicide (ziram) induced intoxication on pathomorphology of broiler chicken. After 2 weeks of age the birds were given fungicide (Ziram) in feed as a single oral dose of 100 mg/kg body weight. Out of 10 birds, 3 died due to ziram intoxication (30% mortality rate). Birds that died rapidly showed pronounced neurological signs like convulsions. The carcasses of ziram intoxicated birds appeared dehydrated and their mucous membrane was pale in colour. Marked vascular congestion was observed in brain on gross examination. The livers showed congestion and haemorrhages with necrotic foci. Kidneys and lungs had ecchymotic haemorrhages and heart revealed gelatinization of pericardium, distention and pericarditis. Atrophy of bursa of Fabricius and thymus; hypertrophy of thyroid was found. Histopathological examination revealed neuronal degeneration and necrosis associated with mild gliosis in brain. Lungs, pericardium and epicardium had severe congestion and there was degeneration with separation of myofibers. Glomeruli were congested and frequently revealed hypercellularity. There were sinusoidal congestion and varying degrees of hepatocellular degeneration. Bursa revealed mild depletion of lymphoid cells in few lobules while as thymus showed hypoplasia with depletion of lymphocytes. Thyroid had mild mononuclear cell infiltration and caecum showed marked necrosis and denudation of the mucosa. In conclusion, the depletion of lymphoid tissue from lymphoid organs was suggestive of immunosuppressive and immunomodulatory effects of ziram toxicity in broiler chicken.

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SUN-260 Dual Role of Carboxypeptidase E in Prohormone Processing and a Novel Neurotrophic Factor Mediating Neuroprotection and Cognitive Functions in Hippocampal CA3 Neurons in Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.100 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Lan Xiao ◽

Vinay Sharma ◽

Leila Toulabi ◽

Xuyu Yang ◽

Cheol Lee ◽

...

Keyword(s):

Neurotrophic Factor ◽

Neuronal Degeneration ◽

Tyrosine Kinase Receptor ◽

Wild Type ◽

Prohormone Processing ◽

Hippocampal Ca3 ◽

Ca3 Neurons ◽

The Brain

Abstract Stress causes release of glucocorticoids from the adrenals which then circulate to the brain. High concentrations glucocorticoid from chronic severe stress results in pathophysiology in the brain, including neuronal degeneration, cell death and cognitive dysfunction, leading to diseases such as Alzheimer Disease and Major Depressive Disorders. Neurotrophic/growth factors such as BDNF, NGF and NT3 have been linked to these pathological conditions. Carboxypeptidase E (CPE), a proneuropeptide/prohormone processing enzyme, also named neurotrophic factor-α1(NFα1) is highly expressed in the stress-vulnerable hippocampal CA3 neurons, and was shown to have neuroprotective activity from in vitro studies. Here we investigated if CPE-NFα1 functions in vivo, independent of its enzymatic activity, and the mechanism underlying its action. We generated knock-in mice expressing a non-enzymatic form of CPE, CPE-E342Q, but not wild-type CPE. The CPE-E342Q mice showed significantly decreased neuropeptide content and exhibited obesity, diabetes and infertility due to lack of prohormone processing activity, similar to CPE-KO mice. However, they showed no hippocampal CA3 degeneration, exhibited neurogenesis in the dentate gyrus, and displayed normal spatial learning and memory, similar to CPE wild-type mice, after weaning stress; unlike CPE-KO mice which showed hippocampal CA3 neuronal degeneration and cognitive deficits. Binding studies showed that radiolabeled CPE bound hippocampal cell membrane specifically, in a saturable manner. Binding of CPE and CPE-E342Q to hippocampal neurons activated Erk signaling and pre-treatment with either of these proteins protected neurons against H2O2- or glutamate-induced neurotoxcity by increasing BCL2 expression. In vitro and in vivo inhibitor studies demonstrated that this neuroprotective effect was independent of tyrosine kinase receptor signaling. Taken together, the data provide evidence that CPE-NFα1 is a unique neurotrophic factor which acts through a non-tyrosine kinase receptor to activate Erk-BCL2 signaling to protect hippocampal CA3 neurons against stress-induced neurodegeneration and maintaining normal cognitive functions in mice.

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IKKβ slows Huntington’s disease progression in R6/1 mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814246116 ◽

2019 ◽

Vol 116 (22) ◽

pp. 10952-10961 ◽

Cited By ~ 4

Author(s):

Joseph Ochaba ◽

Gianna Fote ◽

Marketta Kachemov ◽

Soe Thein ◽

Sylvia Y. Yeung ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuronal Degeneration ◽

Neuronal Injury ◽

Therapeutic Interventions ◽

Striatal Neurons ◽

Microglial Response ◽

Relationship Of ◽

The Impact

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

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Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms21176117 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6117

Author(s):

Petra Hnilicová ◽

Oliver Štrbák ◽

Martin Kolisek ◽

Egon Kurča ◽

Kamil Zeleňák ◽

...

Keyword(s):

Multiple Sclerosis ◽

Magnetic Resonance ◽

Neuronal Degeneration ◽

Metabolic Stress ◽

Pathological Process ◽

Diagnostic Tools ◽

Powerful Analytical Tool ◽

The Central Nervous System ◽

Molecular Aspects

Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1H and phosphorus 31P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.

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Autophagy is Activated In Vivo during Trimethyltin-Induced Apoptotic Neurodegeneration: A Study in the Rat Hippocampus

International Journal of Molecular Sciences ◽

10.3390/ijms21010175 ◽

2019 ◽

Vol 21 (1) ◽

pp. 175 ◽

Cited By ~ 1

Author(s):

Sabrina Ceccariglia ◽

Alessandra Alvino ◽

Aurora Del Fà ◽

Ornella Parolini ◽

Fabrizio Michetti ◽

...

Keyword(s):

Western Blotting ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Neuronal Degeneration ◽

Neuronal Loss ◽

Organotin Compound ◽

Nuclear Antigen ◽

Apoptotic Pathway

Trimethyltin (TMT) is an organotin compound known to produce significant and selective neuronal degeneration and reactive astrogliosis in the rodent central nervous system. Autophagy is the main cellular mechanism for degrading and recycling protein aggregates and damaged organelles, which in different stress conditions, such as starvation, generally improves cell survival. Autophagy is documented in several pathologic conditions, including neurodegenerative diseases. This study aimed to investigate the autophagy and apoptosis signaling pathways in hippocampal neurons of TMT-treated (Wistar) rats to explore molecular mechanisms involved in toxicant-induced neuronal injury. The microtubule-associated protein light chain (LC3, autophagosome marker) and sequestosome1 (SQSTM1/p62) (substrate of autophagy-mediated degradation) expressions were examined by Western blotting at different time points after intoxication. The results demonstrate that the LC3 II/I ratio significantly increased at 3 and 5 days, and that p62 levels significantly decreased at 7 and 14 days. Immunofluorescence images of LC3/neuronal nuclear antigen (NeuN) showed numerous strongly positive LC3 neurons throughout the hippocampus at 3 and 5 days. The terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay indicated an increase in apoptotic cells starting from 5 days after treatment. In order to clarify apoptotic pathway, immunofluorescence images of apoptosis-inducing factor (AIF)/NeuN did not show nuclear translocation of AIF in neurons. Increased expression of cleaved Caspase-3 was revealed at 5–14 days in all hippocampal regions by Western blotting and immunohistochemistry analyses. These data clearly demonstrate that TMT intoxication induces a marked increase in both autophagy and caspase-dependent apoptosis, and that autophagy occurring just before apoptosis could have a potential role in neuronal loss in this experimental model of neurodegeneration.

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DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity

The Journal of Cell Biology ◽

10.1083/jcb.201103153 ◽

2011 ◽

Vol 194 (5) ◽

pp. 751-764 ◽

Cited By ~ 117

Author(s):

Arundhati Sengupta Ghosh ◽

Bei Wang ◽

Christine D. Pozniak ◽

Mark Chen ◽

Ryan J. Watts ◽

...

Keyword(s):

Leucine Zipper ◽

Neuronal Degeneration ◽

Scaffolding Protein ◽

Axon Degeneration ◽

Jnk Signaling ◽

Signaling Complex ◽

Neuronal Populations ◽

Neuronal Homeostasis ◽

Stress Response Pathway

The c-Jun N-terminal kinase (JNK) signaling pathway is essential for neuronal degeneration in multiple contexts but also regulates neuronal homeostasis. It remains unclear how neurons are able to dissociate proapoptotic JNK signaling from physiological JNK activity. In this paper, we show that the mixed lineage kinase dual leucine zipper kinase (DLK) selectively regulates the JNK-based stress response pathway to mediate axon degeneration and neuronal apoptosis without influencing other aspects of JNK signaling. This specificity is dependent on interaction of DLK with the scaffolding protein JIP3 to form a specialized JNK signaling complex. Local activation of DLK-based signaling in the axon results in phosphorylation of c-Jun and apoptosis after redistribution of JNK to the cell body. In contrast, regulation of axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates. DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo.

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Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

Brain ◽

10.1093/brain/awu057 ◽

2014 ◽

Vol 137 (5) ◽

pp. 1496-1513 ◽

Cited By ~ 128

Author(s):

Edward Rockenstein ◽

Silke Nuber ◽

Cassia R. Overk ◽

Kiren Ubhi ◽

Michael Mante ◽

...

Keyword(s):

Neuronal Degeneration

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Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1608576114 ◽

2016 ◽

Vol 114 (2) ◽

pp. 346-351 ◽

Cited By ~ 45

Author(s):

Chunyi Liu ◽

Mei Mei ◽

Qiuling Li ◽

Peristera Roboti ◽

Qianqian Pang ◽

...

Keyword(s):

Golgi Apparatus ◽

Purkinje Cell ◽

Secretory Pathway ◽

Neuronal Degeneration ◽

Cell Loss ◽

Cell Number ◽

Causative Role ◽

Neurodegenerative Process ◽

And Function

The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

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