Synapse elimination during development and disease: immune molecules take centre stage

2010 ◽  
Vol 38 (2) ◽  
pp. 476-481 ◽  
Author(s):  
Dorothy P. Schafer ◽  
Beth Stevens
Keyword(s):  
Nervous System ◽  
Neurodegenerative Disease ◽  
Normal Development ◽  
Developmental Process ◽  
Synaptic Dysfunction ◽  
Synapse Elimination ◽  
Synapse Loss ◽  
Disease States ◽  
Developing Nervous System ◽  
Classical Complement

Synapse elimination is a normal developmental process occurring throughout the central and peripheral nervous systems. Meanwhile, gradual and early loss of synapses is a characteristic that is common to several neurodegenerative disease states. Recent evidence has emerged implicating molecules canonically involved in the immune system and inflammation accompanying neurodegeneration (e.g. classical complement cascade) as important players in the normal elimination of synapses in the developing nervous system. As a result, a question has emerged as to whether mechanisms underlying elimination of synapses during normal development are recapitulated and contribute to early synapse loss and nervous system dysfunction during neurodegenerative disease. The present review explores this possibility and provides a description of many neuroimmune proteins that may participate in the elimination of synapses and synaptic dysfunction in the developing and diseased brain.

scholarly journals The good, the bad, and the opportunities of the complement system in neurodegenerative disease

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Nicole D. Schartz ◽  
Andrea J. Tenner
Keyword(s):  
Nervous System ◽  
Neurodegenerative Disease ◽  
Target Identification ◽  
Disease Stage ◽  
Complement Cascade ◽  
Synapse Elimination ◽  
Complement Components ◽  
Beneficial Effects ◽  
Classical Complement Pathway ◽  
Injured Brain

AbstractThe complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

scholarly journals γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

2020 ◽  
Author(s):  
Lucas Restrepo ◽  
Alison DePew ◽  
Elizabeth Moese ◽  
Stephen Tymanskyj ◽  
Michael Parisi ◽  
...  
Keyword(s):  
Nervous System ◽  
Neurodegenerative Disease ◽  
Cytoskeletal Proteins ◽  
Synaptic Dysfunction ◽  
Synaptic Development ◽  
Behavioral Deficits ◽  
Neuromuscular Synapses ◽  
C Terminus ◽  
Parkinson’S Diseases ◽  
Synaptic Maturation

An emerging feature of neurodegenerative disease is synaptic dysfunction and loss, leading to the suggestion that mechanisms required for synaptic maturation may be linked to disease. Synaptic maturation requires the transmission of signals between nascent synaptic sites and the nucleus, but how these signals are generated is not well understood. We posit that proteolytic cleavage of receptors, which enables their translocation to the nucleus, may be a shared molecular mechanism between the events that promote synaptic maturation and those linked to later-onset disorders of the nervous system, including neurodegenerative disease. Here we show during synaptic development, that cleavage of synaptic maturation molecules requires γ-secretase, a protein complex linked to Alzheimer’s Disease, a devastating neurodegenerative condition, is required for postsynaptic maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to appropriately recruit postsynaptic scaffolding and cytoskeletal proteins, and mutant larvae display behavioral deficits. At the NMJ, γ-secretase promotes synaptic maturation through the cleavage of the Wnt receptor Fz2, and the subsequent entry of its C-terminus into the nucleus. A developmental synaptic role for γ-secretase is also conserved in both the Drosophila central nervous system and mammalian cortical neuron dendrites. Finally, we found that similar maturation defects are evident in fly models for ALS, Alzheimer’s, Huntington’s, and Parkinson’s Diseases. The previously unknown, but conserved, role for γ-secretase coupled with its well-known role in neurodegenerative disease suggest that neurodevelopmental defects may be common to diverse neurodegenerative disease models.

Migratory Neural Crest Cells Phagocytose Cellular Debris in the Developing Nervous System

2019 ◽  
Author(s):  
Yunlu Zhu ◽  
Samantha C. Crowley ◽  
Andrew J. Latimer ◽  
Gwendolyn M. Lewis ◽  
Rebecca Nash ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Cellular Debris ◽  
Developing Nervous System

scholarly journals Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 686
Author(s):  
Maria Concetta Geloso ◽  
Nadia D’Ambrosi
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Death ◽  
Environmental Changes ◽  
Experimental Models ◽  
Synaptic Dysfunction ◽  
Synapse Elimination ◽  
Neurodegenerative Process ◽  
Immune Mediated ◽  
Wide Range ◽  
Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

scholarly journals The Spectrum of Congenital Central Nervous System Anomalies Among Stillborn: An Autopsy Based Study

2021 ◽  
pp. 097275312199016
Author(s):  
S. P. Vinutha ◽  
D. Narayanappa ◽  
G. V. Manjunath ◽  
M. S. Sujatha ◽  
M. C. Sapna Patel ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Congenital Anomalies ◽  
Developmental Process ◽  
Holistic Approach ◽  
Fetal Autopsy ◽  
Exact Test ◽  
Medical College ◽  
Ultrasound Findings ◽  
Cns Anomalies

Background: Congenital central nervous system (CNS) anomalies are the structural or functional abnormalities of the brain and spinal cord that occur during the intrauterine developmental process. Purpose: The present study aims to detect the prevalence of congenital CNS anomalies among stillborn fetuses, the association between congenital anomalies and maternal factors, and also the association between autopsy and ultrasound findings. Methods: This study was conducted on 50 stillborn fetuses, obtained from the Department of Obstetrics and Gynecology at JSS Medical College and Hospital, Mysuru. The fetuses were fixed in 10% formalin and autopsies were performed as per the standard fetal autopsy protocol. The congenital CNS anomalies were studied in detail. Results: CNS anomalies were the most common congenital anomalies observed. Out of the total 50 stillborn fetuses studied, CNS anomalies were found in 17 fetuses and their occurrence was more common among male stillborn than females. Meningomyelocele was the most common anomaly, followed by anencephaly. The other anomalies documented were meningocele, encephalocele, meningoencephalocele, agenesis of the corpus callosum, craniorachischisis, bifid cerebellum with hypoplastic vermis, holoprosencephaly, and sirenomelia. Fisher’s exact test showed a significant association between maternal hypothyroidism and congenital CNS anomalies ( P < .05). The autopsy confirmed the ultrasound findings in 40 (80%) fetuses. There were significant additional findings observed in seven (14%) fetal autopsies and ultrasound diagnosis completely changed in three (6%) cases, after the final autopsy procedure. Conclusion: The fetal autopsy is the single most directly evident investigation, which gives information that changes or significantly improves the clinical diagnosis. A multidisciplinary holistic approach toward pregnancy will help to detect any kind of abnormality in the fetus and thus to take a timely decision toward the management.

Juvenile-onset Neuronal Ceroid-Lipofuscinosis in Rambouillet Sheep

1994 ◽  
Vol 31 (1) ◽  
pp. 48-54 ◽  
Author(s):  
J. F. Edwards ◽  
R. W. Storts ◽  
J. R. Joyce ◽  
J. M. Shelton ◽  
C. S. Menzies
Keyword(s):  
Nervous System ◽  
Neuronal Degeneration ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Disease Process ◽  
Autosomal Recessive Inheritance ◽  
Human Beings ◽  
Juvenile Onset ◽  
Ceroid Lipofuscinosis ◽  
Disease States ◽  
The Brain

Two, 8-month-old Rambouillet half-sister ewes with signs of visual loss and decreased mentation were examined. Ewe No. 1 was necropsied at 10 months of age, and alter being held under observation for a further 6 months, ewe No. 2 was necropsied at 16 months of age. At that time, the ewe was blind and severely depressed. Both ewes had deposition of an autofluorescent lipopigment, identified as ceroid-lipofuscin, in neurons of the brain, spinal cord, eye, and dorsal root ganglia. The disease process was progressive and characterized by deposition of lipopigment with neuronal degeneration and severe fibrillary aslrogliosis. This progressive loss of neurons in the older ewe led to severe retinal degeneration. No pigment was observed in cells outside of the nervous system and eye. Controlled breeding studies have shown that this disease has an autosomal, recessive inheritance. The disease referred to here as juvenile-onset neuronal ceroid-lipofuscinosis of Rambouillet sheep is unlike the majority of the hereditary ceroid-lipofuscinoses that occur in human beings and animals in that only the nervous system is affected. Therefore, this disease could serve as an excellent model for the study of lipopigment deposition that affects the nervous system as a result of various disease states and during aging.

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