scholarly journals Case Report: Synucleinopathy Associated With Phalaris Neurotoxicity in Sheep

2021 ◽  
Vol 8 ◽  
Author(s):  
Mourad Tayebi ◽  
Pedro Pinczowski ◽  
Umma Habiba ◽  
Rizwan Khan ◽  
Monique A. David ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neurodegenerative Disorders ◽  
Lewy Bodies ◽  
Model System ◽  
Neuronal Function ◽  
Immunofluorescence Analysis ◽  
Common Endpoint ◽  
Clear Link ◽  
Plant Poisoning ◽  
Pasture Plants

Chronic intoxication with tryptamine-alkaloid-rich Phalaris species (spp.) pasture plants is known colloquially as Phalaris staggers syndrome, a widely occurring neurological disorder of sheep, cattle, horses, and kangaroos. Of comparative interest, structurally analogous tryptamine-alkaloids cause experimental parkinsonism in primates. This study aimed to investigate the neuropathological changes associated with spontaneous cases of Phalaris staggers in sheep with respect to those encountered in human synucleinopathy. In sheep affected with Phalaris staggers, histological, immunohistochemical, and immunofluorescence analysis revealed significant accumulation of neuromelanin and aggregated α-synuclein in the perikaryon of neurons in the cerebral cortex, thalamus, brainstem, and spinal cord. Neuronal intracytoplasmic Lewy bodies inclusions were not observed in these cases of ovine Phalaris staggers. These important findings established a clear link between synucleinopathy and the neurologic form of Phalaris plant poisoning in sheep, demonstrated in six of six affected sheep. Synucleinopathy is a feature of a number of progressive and fatal neurodegenerative disorders of man and may be a common endpoint of such disorders, which in a variety of ways perturb neuronal function. However, whether primary to the degenerative process or a consequence of it awaits clarification in an appropriate model system.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

scholarly journals Deubiquitylating enzymes in neuronal health and disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fatima Amer-Sarsour ◽  
Alina Kordonsky ◽  
Yevgeny Berdichevsky ◽  
Gali Prag ◽  
Avraham Ashkenazi
Keyword(s):  
Human Brain ◽  
Neurodegenerative Disorders ◽  
Structure And Function ◽  
Pivotal Role ◽  
Protein Homeostasis ◽  
Neuronal Function ◽  
Health And Disease ◽  
And Function

AbstractUbiquitylation and deubiquitylation play a pivotal role in protein homeostasis (proteostasis). Proteostasis shapes the proteome landscape in the human brain and its impairment is linked to neurodevelopmental and neurodegenerative disorders. Here we discuss the emerging roles of deubiquitylating enzymes in neuronal function and survival. We provide an updated perspective on the genetics, physiology, structure, and function of deubiquitylases in neuronal health and disease.

scholarly journals The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

2020 ◽  
pp. jbc.RA120.014415
Author(s):  
Tapas Mukherjee ◽  
Valeria Ramaglia ◽  
Mena Abdel-Nour ◽  
Athanasia A Bianchi ◽  
Jessica Tsalikis ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Distal Colon ◽  
Ubiquitin Proteasome System ◽  
Pathological Feature ◽  
Protein Aggregate ◽  
Sensory Afferents ◽  
Cytosolic Protein ◽  
Eif2α Kinase

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response (cUPR) to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

scholarly journals Lost in a Dream

2019 ◽  
pp. 381-396
Author(s):  
Carlos L. Rodriguez ◽  
Babak Tousi
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorders ◽  
Dementia With Lewy Bodies ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Behavior Disorder ◽  
Sleep Behavior ◽  
The Relationship ◽  
Over Time

Rapid-eye-movement sleep behavior disorder (RBD) is a parasomnia that is closely associated with neurodegenerative disorders. RBD is usually caused by neurodegeneration within the brainstem that disables the system responsible for immobilizing skeletal muscles during REM sleep and thus permits motor neurons to activate these muscles during dreaming. The underlying source of the brainstem neurodegeneration spreads over time to other central nervous system regions until it has sufficiently evolved to permit clinical recognition of the underlying neurodegenerative disorder. Longitudinal follow-up of patients with RBD has demonstrated that most patients subsequently develop some neurodegenerative disorder years later, particularly the synucleinopathies. We review the relationship between RBD and dementia with Lewy bodies, which is one of the synucleinopathies. The management of RBD is reviewed with discussion of the relevant considerations in patients with dementia with Lewy bodies.

Content comparison of the Spinal Cord Injury Model System Database to the ICF Generic Sets and Core Sets for spinal cord injury

Spinal Cord ◽  
2019 ◽  
Vol 57 (12) ◽  
pp. 1023-1030
Author(s):  
Roxanne Maritz ◽  
Kannit Pongpipatpaiboon ◽  
John L. Melvin ◽  
Daniel E. Graves ◽  
Birgit Prodinger
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Model System ◽  
System Database ◽  
Spinal Cord Injury Model ◽  
Injury Model ◽  
Cord Injury ◽  
Core Sets

Pathogenesis of Lewy Body Dementia

2017 ◽  
Author(s):  
Jagan A. Pillai ◽  
James B. Leverenz
Keyword(s):  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Lewy Body ◽  
Genetic Factors ◽  
Lewy Bodies ◽  
Lewy Body Dementia ◽  
Therapeutic Interventions ◽  
Cognitive Changes ◽  
Lewy Neurites ◽  
Neuronal Processes

This chapter discusses the Pathogenesis of Lew Body Dementia. The Lewy body dementias (LBDs) are a spectrum of dementing neurodegenerative disorders underpinned by the pathological accumulation of α- synuclein protein in both intraneuronal inclusions, “Lewy bodies, ” and neuronal processes, “Lewy neurites”. The chapter concludes that, as with other forms of cognitive impairment in the aged, the pathophysiology of cognitive impairment in LBD is likely multifactorial. Although it appears that α- synuclein pathology, particularly in the limbic and neocortical regions are linked to cognitive changes, other pathologies such as AD likely also play a role. Emphasizing the complexity, a number of genetic factors have been implicated in the LBDs, some specifically with associations to the synucleinopathies and some with other pathophysiologic processes. This complexity will need to be considered as therapeutic interventions are evaluated for the LBD.

Studies of the aggregation of an amyloidogenic α-synuclein peptide fragment

2005 ◽  
Vol 33 (5) ◽  
pp. 1113-1115 ◽  
Author(s):  
J. Madine ◽  
A.J. Doig ◽  
A. Kitmitto ◽  
D.A. Middleton
Keyword(s):  
Structural Analysis ◽  
Characteristic Feature ◽  
Neurodegenerative Disorders ◽  
Lewy Bodies ◽  
Structural Features ◽  
Full Length ◽  
Peptide Fragment ◽  
Structural Investigations ◽  
Detailed Structural Analysis ◽  
Β Sheet

The deposition of α-syn (α-synuclein) fibrils in Lewy bodies is a characteristic feature of individuals with neurodegenerative disorders. A peptide comprising the central residues 71–82 of α-syn [α-syn(71–82)] is capable of forming β-sheet-rich, amyloid-like fibrils with similar morphologies to fibrils of the full-length protein, providing a useful model of pathogenic α-syn fibrils that is suitable for detailed structural analysis. We have studied the morphology and gross structural features of α-syn(71–82) fibrils formed under different conditions in order to obtain reliable conditions for producing fibrils for further structural investigations. The results indicate that the rate of aggregation and the morphology of the fibrils formed are sensitive to pH and temperature.

Effects of Dorsal Column Spinal Cord Stimulation (DCS) on Reversibility of Neuronal Function-Experience of Treatment for Vegetative States

1989 ◽  
Vol 12 (4) ◽  
pp. 733-738 ◽  
Author(s):  
TETSUO KANNO ◽  
YOSHIFUMI KAMEL ◽  
TETSUYA YOKOYAMA ◽  
MOTOI SHODA ◽  
HIDEAKI TANJI ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Stimulation ◽  
Dorsal Column ◽  
Neuronal Function

scholarly journals Direct immunocytochemistry with a horseradish peroxidase-conjugated monoclonal antibody against substance P.

1982 ◽  
Vol 30 (12) ◽  
pp. 1211-1216 ◽  
Author(s):  
D M Boorsma ◽  
A C Cuello ◽  
F W van Leeuwen
Keyword(s):  
Spinal Cord ◽  
Monoclonal Antibody ◽  
Substance P ◽  
Horseradish Peroxidase ◽  
Nerve Fibers ◽  
Model System ◽  
Gel Chromatography ◽  
Rat Spinal Cord ◽  
Fixed Tissue ◽  
Triton X

The procedure for the isolation and conjugation of the anti-substance P monoclonal antibody NC1/34 with the enzyme horseradish peroxidase (HRP) is described. This resulted in a molecular complex of monoclonal antibody/HRP of 1:1. This conjugate was of approximately 400,000 daltons, as estimated by gel chromatography. Practically all the isolated antibody was coupled to HRP. The conjugate was tested both in a model system where CNBr-activated Sepharose beads were coupled to substance P and on fixed tissue preparations from the rat spinal cord and medulla oblongata. The conjugate revealed staining in nerve fibers in areas known to contain substance P. The best immunohistochemical results were obtained by prolonged incubations at 12 degrees C in the presence of 0.1% Triton X-100. The preabsorption of the conjugate with substance P obliterated the reaction.

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