scholarly journals Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1678
Author(s):  
Liriopé Toupenet Marchesi ◽  
Marion Leblanc ◽  
Giovanni Stevanin
Keyword(s):  
Nervous System ◽  
Motor Neurons ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Current Knowledge ◽  
Spastic Paraplegia ◽  
Functional Convergence ◽  
The Common ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

scholarly journals Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery

2021 ◽  
Vol 11 (3) ◽  
pp. 403
Author(s):  
Alan Mackay-Sim
Keyword(s):  
Motor Neurons ◽  
Hereditary Spastic Paraplegia ◽  
Genetic Disorders ◽  
Spastic Paraplegia ◽  
Cellular Mechanisms ◽  
Causative Gene ◽  
Cell Functions ◽  
Daunting Task ◽  
Future Drug ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) is a diverse group of Mendelian genetic disorders affecting the upper motor neurons, specifically degeneration of their distal axons in the corticospinal tract. Currently, there are 80 genes or genomic loci (genomic regions for which the causative gene has not been identified) associated with HSP diagnosis. HSP is therefore genetically very heterogeneous. Finding treatments for the HSPs is a daunting task: a rare disease made rarer by so many causative genes and many potential mutations in those genes in individual patients. Personalized medicine through genetic correction may be possible, but impractical as a generalized treatment strategy. The ideal treatments would be small molecules that are effective for people with different causative mutations. This requires identification of disease-associated cell dysfunctions shared across genotypes despite the large number of HSP genes that suggest a wide diversity of molecular and cellular mechanisms. This review highlights the shared dysfunctional phenotypes in patient-derived cells from patients with different causative mutations and uses bioinformatic analyses of the HSP genes to identify novel cell functions as potential targets for future drug treatments for multiple genotypes.

A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration

2020 ◽  
Vol 31 (4) ◽  
pp. 351-362 ◽  
Author(s):  
Alessio Guglielmi
Keyword(s):  
Neurodegenerative Diseases ◽  
Sigmund Freud ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Dna Analysis ◽  
Therapeutic Strategies ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Adolf Von Strümpell

AbstractAt the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3–9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.

scholarly journals Myosin XVI in the Nervous System

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1903
Author(s):  
Elek Telek ◽  
András Kengyel ◽  
Beáta Bugyi
Keyword(s):  
Nervous System ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Structural Features ◽  
Neural Cells ◽  
Cellular Functions ◽  
Cytoskeleton Reorganization ◽  
Neural Tissues ◽  
Cell Signaling Pathways

The myosin family is a large inventory of actin-associated motor proteins that participate in a diverse array of cellular functions. Several myosin classes are expressed in neural cells and play important roles in neural functioning. A recently discovered member of the myosin superfamily, the vertebrate-specific myosin XVI (Myo16) class is expressed predominantly in neural tissues and appears to be involved in the development and proper functioning of the nervous system. Accordingly, the alterations of MYO16 has been linked to neurological disorders. Although the role of Myo16 as a generic actin-associated motor is still enigmatic, the N-, and C-terminal extensions that flank the motor domain seem to confer unique structural features and versatile interactions to the protein. Recent biochemical and physiological examinations portray Myo16 as a signal transduction element that integrates cell signaling pathways to actin cytoskeleton reorganization. This review discusses the current knowledge of the structure-function relation of Myo16. In light of its prevalent localization, the emphasis is laid on the neural aspects.

scholarly journals Fulgence Raymond (1844–1910), regrettably forgotten successor of Jean-Martin Charcot

2019 ◽  
Vol 3 (2) ◽  
pp. 2514183X1988038 ◽  
Author(s):  
Olivier Walusinski
Keyword(s):  
Nervous System ◽  
Hereditary Spastic Paraplegia ◽  
Current Knowledge ◽  
Nervous System Diseases ◽  
Spastic Paraplegia ◽  
Relevant Today ◽  
Biographical Account ◽  
Jean Martin Charcot

Fulgence Raymond (1844–1910) succeeded Jean-Martin Charcot (1825–1893) to the Chair of Nervous System Diseases. As famous as Charcot remains, Raymond has been forgotten. After a brief biographical account, we will present a few examples of his work still relevant today: hemichorea, Raymond-Cestan syndrome, hereditary spastic paraplegia and acute ascendant paralysis. In each case, his accurate clinical and anatomopathological descriptions are accompanied by aetiological hypotheses that are remarkably prescient with regard to current knowledge. Strongly committed to teaching, he published most of his lessons every year. They remain highly relevant historically, and sometimes for other reasons, as we shall see. We hope to show that Raymond does not deserve to be forgotten.

scholarly journals Mouse models for hereditary spastic paraplegia uncover a role of PI4K2A in autophagic lysosome reformation

Autophagy ◽  
2021 ◽  
pp. 1-17
Author(s):  
Mukhran Khundadze ◽  
Federico Ribaudo ◽  
Adeela Hussain ◽  
Henry Stahlberg ◽  
Nahal Brocke-Ahmadinejad ◽  
...  
Keyword(s):  
Mouse Models ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

scholarly journals Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Banglian Hu ◽  
Shengshun Duan ◽  
Ziwei Wang ◽  
Xin Li ◽  
Yuhang Zhou ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Colony Stimulating Factor ◽  
Loss Of Function ◽  
Axonal Spheroids ◽  
The Central Nervous System ◽  
Stimulating Factor

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

scholarly journals Store-Operated Calcium Channels in Physiological and Pathological States of the Nervous System

2020 ◽  
Vol 14 ◽  
Author(s):  
Isis Zhang ◽  
Huijuan Hu
Keyword(s):  
Nervous System ◽  
Calcium Channels ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Physiological Role ◽  
The Body ◽  
Store Operated Calcium Entry ◽  
Important Pathway ◽  
Molecular Components

Store-operated calcium channels (SOCs) are widely expressed in excitatory and non-excitatory cells where they mediate significant store-operated calcium entry (SOCE), an important pathway for calcium signaling throughout the body. While the activity of SOCs has been well studied in non-excitable cells, attention has turned to their role in neurons and glia in recent years. In particular, the role of SOCs in the nervous system has been extensively investigated, with links to their dysregulation found in a wide variety of neurological diseases from Alzheimer’s disease (AD) to pain. In this review, we provide an overview of their molecular components, expression, and physiological role in the nervous system and describe how the dysregulation of those roles could potentially lead to various neurological disorders. Although further studies are still needed to understand how SOCs are activated under physiological conditions and how they are linked to pathological states, growing evidence indicates that SOCs are important players in neurological disorders and could be potential new targets for therapies. While the role of SOCE in the nervous system continues to be multifaceted and controversial, the study of SOCs provides a potentially fruitful avenue into better understanding the nervous system and its pathologies.

miRNAs in development and pathogenesis of the nervous system

2013 ◽  
Vol 41 (4) ◽  
pp. 815-820 ◽  
Author(s):  
Jakub S. Nowak ◽  
Gracjan Michlewski
Keyword(s):  
Nervous System ◽  
Present Article ◽  
Neurodevelopmental Disorders ◽  
Current Knowledge ◽  
And Function ◽  
Human Nervous System

The human nervous system expresses approximately 70% of all miRNAs (microRNAs). Changing levels of certain ubiquitous and brain-specific miRNAs shape the development and function of the nervous system. It is becoming clear that misexpression of some miRNAs can contribute towards neurodevelopmental disorders. In the present article, we review the current knowledge of the role of miRNAs in development and pathogenesis of the nervous system.

scholarly journals Neural Control of Immunity in Hypertension: Council on Hypertension Mid Career Award for Research Excellence, 2019

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 622-628
Author(s):  
Daniela Carnevale
Keyword(s):  
Immune Response ◽  
Nervous System ◽  
Neural Control ◽  
Neural Signals ◽  
The Past ◽  
Target Organs ◽  
Long Time ◽  
The Common ◽  
The Brain

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these 2 evolutionarily highly conserved systems has been recognized for long time, the investigation into the pathophysiological mechanisms underlying their crosstalk has been tackled only in recent decades. Recent work of the past years elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. This review will focus on the neural mechanisms regulating the immune response and the role of this neuroimmune crosstalk in hypertension. In this context, the review highlights the components of the brain-spleen axis with a focus on the neuroimmune interface established in the spleen, where neural signals shape the immune response recruited to target organs of high blood pressure.

scholarly journals BDNF signaling during the lifetime of dendritic spines

2020 ◽  
Vol 382 (1) ◽  
pp. 185-199 ◽  
Author(s):  
Marta Zagrebelsky ◽  
Charlotte Tacke ◽  
Martin Korte
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Neurological Disorders ◽  
Current Knowledge ◽  
Conclusive Evidence ◽  
Excitatory Synapses ◽  
Neuronal Homeostasis ◽  
Bdnf Signaling ◽  
Spine Number

Abstract Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

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