scholarly journals JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
N. M. Rafiq ◽  
L. L. Lyons ◽  
S. Gowrishankar ◽  
P. De Camilli ◽  
S. M. Ferguson
Keyword(s):  
Neurodegenerative Diseases ◽  
Axonal Transport ◽  
Neurological Disease ◽  
Myosin Ii ◽  
Microtubule Organization ◽  
Multiple Components ◽  
Axonal Cytoskeleton ◽  
Human Neurons ◽  
The Impact ◽  
Axonal Swellings

AbstractLysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling. This local axonal microtubule disorganization was accompanied by accumulations of both F-actin and myosin II. These results indicate that transport of axonal lysosomes is functionally interconnected with mechanisms that control the organization and maintenance of the axonal cytoskeleton. They have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative diseases associated with the focal accumulations of lysosomes within axonal swellings such as Alzheimer’s disease.

scholarly journals JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

2020 ◽  
Author(s):  
N.M. Rafiq ◽  
L.L. Lyons ◽  
S. Gowrishankar ◽  
P. De Camilli ◽  
S.M. Ferguson
Keyword(s):  
Alzheimer’S Disease ◽  
Axonal Transport ◽  
Neurological Disease ◽  
Myosin Ii ◽  
Microtubule Organization ◽  
Multiple Components ◽  
Axonal Cytoskeleton ◽  
Human Neurons ◽  
The Impact ◽  
Axonal Swellings

AbstractLysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling. This axonal microtubule disorganization in JIP3 KO neurons was accompanied by increased tau abundance and phosphorylation. These results indicate that transport of axonal lysosomes is integrated into a much larger network that is required for the maintenance of the axonal cytoskeleton. These findings have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative tauopathies such as Alzheimer’s disease.

Diagnostic tools for evaluating the impact of Focal Axonal Swellings arising in neurodegenerative diseases and/or traumatic brain injury

2015 ◽  
Vol 253 ◽  
pp. 233-243 ◽  
Author(s):  
Pedro D. Maia ◽  
Matthew A. Hemphill ◽  
Brendan Zehnder ◽  
Chenfei Zhang ◽  
Kevin K. Parker ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurodegenerative Diseases ◽  
Diagnostic Tools ◽  
The Impact ◽  
Axonal Swellings

scholarly journals Roles of Microglial Ion Channel in Neurodegenerative Diseases

2021 ◽  
Vol 10 (6) ◽  
pp. 1239
Author(s):  
Alexandru Cojocaru ◽  
Emilia Burada ◽  
Adrian-Tudor Bălșeanu ◽  
Alexandru-Florian Deftu ◽  
Bogdan Cătălin ◽  
...  
Keyword(s):  
Ion Channels ◽  
Neurodegenerative Diseases ◽  
Excitable Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Common ◽  
Transient Receptor ◽  
The Impact

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

scholarly journals Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Dunhui Li ◽  
Craig Stewart McIntosh ◽  
Frank Louis Mastaglia ◽  
Steve Donald Wilton ◽  
May Thandar Aung-Htut
Keyword(s):  
Alternative Splicing ◽  
Neurodegenerative Diseases ◽  
Messenger Rna ◽  
Muscular Atrophy ◽  
Single Gene ◽  
Synaptic Function ◽  
Coding Regions ◽  
Splicing Defects ◽  
The Impact ◽  
Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

Mechanisms of neuronal death in disease: defining the models and the players

2008 ◽  
Vol 415 (2) ◽  
pp. 165-182 ◽  
Author(s):  
Elena M. Ribe ◽  
Esther Serrano-Saiz ◽  
Nsikan Akpan ◽  
Carol M. Troy
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Death ◽  
Neurological Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Level ◽  
Therapeutic Interventions ◽  
Common Cause ◽  
Life And Death ◽  
Caspase Family ◽  
Common Neurodegenerative Disorder

Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.

scholarly journals Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Monica Frega ◽  
Katrin Linda ◽  
Jason M. Keller ◽  
Güvem Gümüş-Akay ◽  
Britt Mossink ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Cortical Neurons ◽  
Neurodevelopmental Disorder ◽  
Control Networks ◽  
Human Neurons ◽  
Kleefstra Syndrome ◽  
Nmdar Subunit ◽  
Induced Pluripotent ◽  
Reduced Rate ◽  
The Impact

Abstract Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS.

scholarly journals Aerobic or strength training and flexibility activities and mild cognitive impairment: CETI cohort

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
C Dupré ◽  
B Bongue ◽  
L Fruteau de Laclos ◽  
J Blais ◽  
M-J Sirois
Keyword(s):  
Physical Activity ◽  
Cognitive Impairment ◽  
Neurodegenerative Diseases ◽  
Cognitive Impairments ◽  
Cognitive Status ◽  
Physical Activities ◽  
Community Dwelling ◽  
Different Types ◽  
Initiative Program ◽  
The Impact

Abstract Background Previous studies have been notably criticized for not studying the different types of physical activity. The objective of this work was to examine the association between types of physical activity and cognitive decline in older people. Methods This is a sub-group analysis from the CETI cohort, a multicenter prospective study conducted by the Canadian Emergency Team Initiative Program (CETIE), between 2011 and 2016. Participants were community-dwelling seniors aged ≥ 65 years, consult emergency services for minor injuries with follow-up at 3 and 6 months. Physical activity was assessed by the RAPA (Rapid assessment of Physical activity), which describes the level of aerobic activities and the overall level of muscle strength and flexibility activities. The cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) and the Telephone Interview for Cognitive Status (TICS), using their current cut-offs (MoCA <26/30 and TICS < = 35/50) for mild cognitive impairments (MCI). Logistic regression, COX models and splines were used to examine the association between the type of physical activities and the onset of cognitive impairment. Results At inclusion, 281 individuals were free of MCI, or 43.8% of the total sample, with an average age of 73 years. During follow-ups, MCI appeared in 31.7% of participants initially free of it. The risk of MCI was lower with higher muscular strength & flexibility physical activities (HR = 0.84 [0.70-0.99]), while the relationship with aerobic physical activities was not significant. Conclusions These results showed a potential link between strength & flexibility activities and cognitive impairments, but not with aerobic physical activities. Further analyses are needed to examine whether these relationships persist as a function of the adjustment variables, or statistical methods. This study contributes to the debate on the evaluation of physical activity in the elderly, and its link with neurodegenerative diseases. Key messages This study analyzed the link between types of physical activity and mild cognitive disorders. The aim is to put in place preventive policies of aging, specially in neurodegenerative diseases. The work allowed us to see the effect of the different types of physical activity and the impact of the statistical method on the results.

scholarly journals Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reducedα-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Nikolaus Berndt ◽  
Sascha Bulik ◽  
Hermann-Georg Holzhütter
Keyword(s):  
Reactive Oxygen Species ◽  
Neurodegenerative Diseases ◽  
Neuronal Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Dependent Inactivation ◽  
The Impact ◽  
Ketoglutarate Dehydrogenase

Reduced activity of brain α-ketoglutarate dehydrogenase complex (KGDHC) occurs in a number of neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. In order to quantify the relation between diminished KGDHC activity and the mitochondrial ATP generation, redox state, transmembrane potential, and generation of reactive oxygen species (ROS) by the respiratory chain (RC), we developed a detailed kinetic model. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. By contrast, progressive inhibition of the enzyme aconitase had only little impact on these mitochondrial parameters. As KGDHC is susceptible to ROS-dependent inactivation, we also investigated the reduction state of those sites of the RC proposed to be involved in ROS production. The reduction state of all sites except one decreased with increasing degree of KGDHC inhibition suggesting an ROS-reducing effect of KGDHC inhibition. Our model underpins the important role of reduced KGDHC activity in the energetic breakdown of neuronal cells during development of neurodegenerative diseases.

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