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Brain Sciences
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Factors Responsible for CSMN Vulnerability
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Factors Responsible for CSMN Vulnerability

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuroglia".

Deadline for manuscript submissions: closed (2 April 2021) | Viewed by 70354

Special Issue Editors

Dr. P. Hande Ozdinler

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Guest Editor
Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Interests: upper motor neuron biology; motor neuron diseases; ALS; HSP; PLS; drug development; preclinical studies; modeling motor neuron diseases
Dr. Bradley Turner

E-Mail Website
Guest Editor
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
Interests: chronic neurodegenerative diseases; amyotrophic lateral sclerosis; motor neuron disease; spinal bulbar muscular atrophy; spinal muscular atrophy; motor neurons; glial cells; induced pluripotent stem cells; transgenic mouse models; human post-mortem tissue, autophagy; cell death pathways; necroptosis; ferroptosis; protein misfolding and aggregation; neuroinflammation; lipidomics

Special Issue Information

Dear Colleagues,

The movement starts in the brain. Upper motor neurons reside in layer V of the motor cortex and they have a unique function for the initiation and modulation of voluntary movement: they collect and integrate cortical input, and translate that information into a signal that is sent to appropriate spinal targets.  Their ability to connect brain with the spinal cord and to convey cerebral cortex’s input to spinal cord targets enable execution of very precise aspects of voluntary movement.  Therefore, it is no surprise that these neurons populations are clinically important.

Their degeneration leads to numerous motor neuron diseases, such as primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and they degenerate together with spinal motor neurons in amyotrophic lateral sclerosis (ALS).  In addition, upper motor neuron death eventually leads to long-term paralysis in spinal cord injury patients.  Therefore, even though this neuron population is clinically relevant both within the context of neurodegeneration and injury, their biology and pathology have not received the attention they deserve. 

In this special issue, our goal is to present the current developments in the field of upper motor neuron biology both within the context of health and disease.  When the basis of their selective vulnerability in diseases is revealed, and when effective treatment strategies that improve their health and function are developed, we will begin to build long-term solutions to many of the motor neuron diseases.    

As the importance of upper motor neurons is being appreciated, this special issue brings prominent scientists and clinicians together and generates a platform for novel findings. We thank you for your contribution and interest.

Dr. P. Hande Ozdinler
Dr. Bradley Turner
Guest Editors

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Research

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17 pages, 4497 KiB  
Article
Differential NPY-Y1 Receptor Density in the Motor Cortex of ALS Patients and Familial Model of ALS
by Courtney M. Clark, Rosemary M. Clark, Joshua A. Hoyle, Jyoti A. Chuckowree, Catriona A. McLean and Tracey C. Dickson
Brain Sci. 2021, 11(8), 969; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11080969 - 23 Jul 2021
Cited by 2 | Viewed by 2670
Abstract
Destabilization of faciliatory and inhibitory circuits is an important feature of corticomotor pathology in amyotrophic lateral sclerosis (ALS). While GABAergic inputs to upper motor neurons are reduced in models of the disease, less understood is the involvement of peptidergic inputs to upper motor [...] Read more.
Destabilization of faciliatory and inhibitory circuits is an important feature of corticomotor pathology in amyotrophic lateral sclerosis (ALS). While GABAergic inputs to upper motor neurons are reduced in models of the disease, less understood is the involvement of peptidergic inputs to upper motor neurons in ALS. The neuropeptide Y (NPY) system has been shown to confer neuroprotection against numerous pathogenic mechanisms implicated in ALS. However, little is known about how the NPY system functions in the motor system. Herein, we investigate post-synaptic NPY signaling on upper motor neurons in the rodent and human motor cortex, and on cortical neuron populations in vitro. Using immunohistochemistry, we show the increased density of NPY-Y1 receptors on the soma of SMI32-positive upper motor neurons in post-mortem ALS cases and SOD1G93A excitatory cortical neurons in vitro. Analysis of receptor density on Thy1-YFP-H-positive upper motor neurons in wild-type and SOD1G93A mouse tissue revealed that the distribution of NPY-Y1 receptors was changed on the apical processes at early-symptomatic and late-symptomatic disease stages. Together, our data demonstrate the differential density of NPY-Y1 receptors on upper motor neurons in a familial model of ALS and in ALS cases, indicating a novel pathway that may be targeted to modulate upper motor neuron activity. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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16 pages, 5544 KiB  
Article
Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons
by Marcus S. Dyer, Adele Woodhouse and Catherine A. Blizzard
Brain Sci. 2021, 11(7), 883; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11070883 - 30 Jun 2021
Cited by 9 | Viewed by 3723
Abstract
Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in [...] Read more.
Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliest detectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigated how mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracycline inducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannot enter the nucleus (TDP-43ΔNLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH mice to visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WT and controls, TDP-43ΔNLS drove a robust loss in spine density in all the dendrite regions of the upper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in the generation of network dysfunction in ALS likely through impacting the formation or durability of excitatory synapses. These findings are relevant to the vast majority of ALS cases, and provides further evidence that upper motor neurons may need to be protected from TDP-43 mediated synaptic excitatory changes early in disease. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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9 pages, 716 KiB  
Article
Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
by Reham Khalaf-Nazzal, James Fasham, Nishanka Ubeyratna, David J. Evans, Joseph S. Leslie, Thomas T. Warner, Fida’ Al-Hijawi, Shurouq Alshaer, Wisam Baker, Peter D. Turnpenny, Emma L. Baple and Andrew H. Crosby
Brain Sci. 2021, 11(5), 614; https://doi.org/10.3390/brainsci11050614 - 11 May 2021
Cited by 4 | Viewed by 3013
Abstract
The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a [...] Read more.
The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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15 pages, 3906 KiB  
Article
Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS
by Oge Gozutok, Benjamin Ryan Helmold and P. Hande Ozdinler
Brain Sci. 2021, 11(5), 578; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11050578 - 29 Apr 2021
Cited by 2 | Viewed by 2326
Abstract
Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations [...] Read more.
Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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18 pages, 19250 KiB  
Article
Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis
by Christine Marques, Thibaut Burg, Jelena Scekic-Zahirovic, Mathieu Fischer and Caroline Rouaux
Brain Sci. 2021, 11(3), 369; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11030369 - 13 Mar 2021
Cited by 16 | Viewed by 3564
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: (i) are the degenerations of these two neuronal populations somatotopically related? and if yes (ii), where does neurodegeneration start? If studies carried out on ALS patients clearly demonstrated the somatotopic relationship between UMN and LMN degenerations, their temporal relationship remained an unanswered question. In the present study, we took advantage of the well-described Sod1G86R model of ALS to interrogate the somatotopic and temporal relationships between UMN and LMN degenerations in ALS. Using retrograde labelling from the cervical or lumbar spinal cord of Sod1G86R mice and controls to identify UMN, along with electrophysiology and histology to assess LMN degeneration, we applied rigorous sampling, counting, and statistical analyses, and show that UMN and LMN degenerations are somatotopically related and that UMN depletion precedes LMN degeneration. Together, the data indicate that UMN degeneration is a particularly early and thus relevant event in ALS, in accordance with a possible cortical origin of the disease, and emphasize the need to further elucidate the molecular mechanisms behind UMN degeneration, towards new therapeutic avenues. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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13 pages, 15723 KiB  
Article
Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents
by Mor R. Alkaslasi, Noell E. Cho, Navpreet K. Dhillon, Oksana Shelest, Patricia S. Haro-Lopez, Nikhil T. Linaval, Josh Ghoulian, Audrey R. Yang, Jean-Philippe Vit, Pablo Avalos, Eric J. Ley and Gretchen M. Thomsen
Brain Sci. 2021, 11(2), 160; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11020160 - 26 Jan 2021
Cited by 6 | Viewed by 2459
Abstract
Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate [...] Read more.
Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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Review

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10 pages, 761 KiB  
Review
Advances in Gene Delivery Methods to Label and Modulate Activity of Upper Motor Neurons: Implications for Amyotrophic Lateral Sclerosis
by Mouna Haidar, Aida Viden and Bradley J. Turner
Brain Sci. 2021, 11(9), 1112; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11091112 - 24 Aug 2021
Viewed by 2866
Abstract
The selective degeneration of both upper motor neurons (UMNs) and lower motor neurons (LMNs) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Unlike the simple organisation of LMNs in the brainstem and spinal cord, UMNs are embedded in the complex cytoarchitecture of [...] Read more.
The selective degeneration of both upper motor neurons (UMNs) and lower motor neurons (LMNs) is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Unlike the simple organisation of LMNs in the brainstem and spinal cord, UMNs are embedded in the complex cytoarchitecture of the primary motor cortex, which complicates their identification. UMNs therefore remain a challenging neuronal population to study in ALS research, particularly in the early pre-symptomatic stages of animal models. A better understanding of the mechanisms that lead to selective UMN degeneration requires unequivocal visualization and cellular identification of vulnerable UMNs within the heterogeneous cortical neuronal population and circuitry. Here, we review recent novel gene delivery methods developed to cellularly identify vulnerable UMNs and modulate their activity in various mouse models. A critical overview of retrograde tracers, viral vectors encoding reporter genes and transgenic reporter mice used to visualize UMNs in mouse models of ALS is provided. Functional targeting of UMNs in vivo with the advent of optogenetic and chemogenetic technology is also discussed. These exciting gene delivery techniques will facilitate improved anatomical mapping, cell-specific gene expression profiling and targeted manipulation of UMN activity in mice. These advancements in the field pave the way for future work to uncover the precise role of UMNs in ALS and improve future therapeutic targeting of UMNs. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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9 pages, 952 KiB  
Review
Therapeutic Strategies for Mutant SPAST-Based Hereditary Spastic Paraplegia
by Neha Mohan, Liang Qiang, Gerardo Morfini and Peter W. Baas
Brain Sci. 2021, 11(8), 1081; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11081081 - 18 Aug 2021
Cited by 4 | Viewed by 4111
Abstract
Mutations of the SPAST gene that encodes the microtubule-severing enzyme called spastin are the chief cause of Hereditary Spastic Paraplegia. Growing evidence indicates that pathogenic mutations functionally compromise the spastin protein and endow it with toxic gain-of-function properties. With each of these two [...] Read more.
Mutations of the SPAST gene that encodes the microtubule-severing enzyme called spastin are the chief cause of Hereditary Spastic Paraplegia. Growing evidence indicates that pathogenic mutations functionally compromise the spastin protein and endow it with toxic gain-of-function properties. With each of these two factors potentially relevant to disease etiology, the present article discusses possible therapeutic strategies that may ameliorate symptoms in patients suffering from SPAST-based Hereditary Spastic Paraplegia, which is usually termed SPG4-HSP. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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12 pages, 286 KiB  
Review
The Upper Motor Neuron—Improved Knowledge from ALS and Related Clinical Disorders
by Parvathi Menon and Steve Vucic
Brain Sci. 2021, 11(8), 958; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11080958 - 21 Jul 2021
Cited by 2 | Viewed by 4431
Abstract
Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary [...] Read more.
Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary movement of the musculoskeletal system by pathways which are not completely understood. Dysfunction of the upper motor neuron causes the classical clinical signs of spasticity, weakness, brisk tendon reflexes and extensor plantar response, which are associated with clinically well-recognised, inherited and acquired disorders of the nervous system. Understanding the pathophysiology of motor system dysfunction in neurological disease has helped promote a greater understanding of the motor system and its complex cortical connections. This review will focus on the pathophysiology underlying progressive dysfunction of the UMN in amyotrophic lateral sclerosis and three other related adult-onset, progressive neurological disorders with prominent UMN signs, namely, primary lateral sclerosis, hereditary spastic paraplegia and primary progressive multiple sclerosis, to help promote better understanding of the human motor system and, by extension, related cortical systems. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
10 pages, 270 KiB  
Review
Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis
by Nimeshan Geevasinga, Mehdi Van den Bos, Parvathi Menon and Steve Vucic
Brain Sci. 2021, 11(7), 906; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11070906 - 09 Jul 2021
Cited by 5 | Viewed by 2819
Abstract
Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes [...] Read more.
Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
12 pages, 798 KiB  
Review
Cortical Excitability across the ALS Clinical Motor Phenotypes
by Thanuja Dharmadasa
Brain Sci. 2021, 11(6), 715; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11060715 - 28 May 2021
Cited by 5 | Viewed by 5292
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a [...] Read more.
Amyotrophic lateral sclerosis (ALS) is characterized by its marked clinical heterogeneity. Although the coexistence of upper and lower motor neuron signs is a common clinical feature for most patients, there is a wide range of atypical motor presentations and clinical trajectories, implying a heterogeneity of underlying pathogenic mechanisms. Corticomotoneuronal dysfunction is increasingly postulated as the harbinger of clinical disease, and neurophysiological exploration of the motor cortex in vivo using transcranial magnetic stimulation (TMS) has suggested that motor cortical hyperexcitability may be a critical pathogenic factor linked to clinical features and survival. Region-specific selective vulnerability at the level of the motor cortex may drive the observed differences of clinical presentation across the ALS motor phenotypes, and thus, further understanding of phenotypic variability in relation to cortical dysfunction may serve as an important guide to underlying disease mechanisms. This review article analyses the cortical excitability profiles across the clinical motor phenotypes, as assessed using TMS, and explores this relationship to clinical patterns and survival. This understanding will remain essential to unravelling central disease pathophysiology and for the development of specific treatment targets across the ALS clinical motor phenotypes. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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10 pages, 558 KiB  
Review
The Cortical “Upper Motoneuron” in Health and Disease
by Roger N. Lemon
Brain Sci. 2021, 11(5), 619; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11050619 - 12 May 2021
Cited by 13 | Viewed by 2238
Abstract
Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre [...] Read more.
Upper motoneurons (UMNs) in motor areas of the cerebral cortex influence spinal and cranial motor mechanisms through the corticospinal tract (CST) and through projections to brainstem motor pathways. The primate corticospinal system has a diverse cortical origin and a wide spectrum of fibre diameters, including large diameter fibres which are unique to humans and other large primates. Direct cortico-motoneuronal (CM) projections from the motor cortex to arm and hand motoneurons are a late evolutionary feature only present in dexterous primates and best developed in humans. CM projections are derived from a more restricted cortical territory (‘new’ M1, area 3a) and arise not only from corticospinal neurons with large, fast axons but also from those with relatively slow-conducting axons. During movement, corticospinal neurons are organised and recruited quite differently from ‘lower’ motoneurons. Accumulating evidence strongly implicates the corticospinal system in the early stages of ALS, with particular involvement of CM projections to distal limb muscles, but also to other muscle groups influenced by the CM system. There are important species differences in the organisation and function of the corticospinal system, and appropriate animal models are needed to understand disorders involving the human corticospinal system. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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13 pages, 254 KiB  
Review
Upper Motor Neuron Disorders: Primary Lateral Sclerosis, Upper Motor Neuron Dominant Amyotrophic Lateral Sclerosis, and Hereditary Spastic Paraplegia
by Timothy Fullam and Jeffrey Statland
Brain Sci. 2021, 11(5), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11050611 - 11 May 2021
Cited by 6 | Viewed by 7801
Abstract
Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early [...] Read more.
Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early phases of disease remains challenging. While no single clinical or diagnostic tests is specific, there are several developing biomarkers and neuroimaging technologies which may help distinguish PLS from HSP and UMNdALS. Recent consensus diagnostic criteria and use of evolving technologies will allow more precise delineation of PLS from other upper motor neuron disorders and aid in the targeting of potentially disease-modifying therapeutics. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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10 pages, 298 KiB  
Review
Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review
by Jonu Pradhan and Mark C. Bellingham
Brain Sci. 2021, 11(5), 549; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11050549 - 27 Apr 2021
Cited by 8 | Viewed by 2679
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neuromotor disease characterized by the loss of upper and lower motor neurons (MNs), resulting in muscle paralysis and death. Early cortical hyper-excitability is a common pathological process observed clinically and in animal disease models. Although the mechanisms that underlie cortical hyper-excitability are not completely understood, the molecular and cellular mechanisms that cause enhanced neuronal intrinsic excitability and changes in excitatory and inhibitory synaptic activity are starting to emerge. Here, we review the evidence for an anterograde glutamatergic excitotoxic process, leading to cortical hyper-excitability via intrinsic cellular and synaptic mechanisms and for the role of interneurons in establishing disinhibition in clinical and experimental settings. Understanding the mechanisms that lead to these complex pathological processes will likely produce key insights towards developing novel therapeutic strategies to rescue upper MNs, thus alleviating the impact of this fatal disease. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
23 pages, 8962 KiB  
Review
Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery
by Alan Mackay-Sim
Brain Sci. 2021, 11(3), 403; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11030403 - 22 Mar 2021
Cited by 25 | Viewed by 4204
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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9 pages, 551 KiB  
Review
The Dying Forward Hypothesis of ALS: Tracing Its History
by Andrew Eisen
Brain Sci. 2021, 11(3), 300; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11030300 - 27 Feb 2021
Cited by 32 | Viewed by 7037
Abstract
The site of origin of amyotrophic lateral sclerosis (ALS), although unsettled, is increasingly recognized as being cortico-fugal, which is a dying-forward process primarily starting in the corticomotoneuronal system. A variety of iterations of this concept date back to over 150 years. Recently, the [...] Read more.
The site of origin of amyotrophic lateral sclerosis (ALS), although unsettled, is increasingly recognized as being cortico-fugal, which is a dying-forward process primarily starting in the corticomotoneuronal system. A variety of iterations of this concept date back to over 150 years. Recently, the hallmark TAR DNA-binding protein 43 (TDP-43) pathology, seen in >95% of patients with ALS, has been shown to be largely restricted to corticofugal projecting neurons (“dying forward”). Possibly, soluble but toxic cytoplasmic TDP-43 could enter the axoplasm of Betz cells, subsequently causing dysregulation of nuclear protein in the lower brainstem and spinal cord anterior horn cells. As the disease progresses, cortical involvement in ALS becomes widespread, including or starting with frontotemporal dementia, implying a broader view of ALS as a brain disease. The onset at the motor and premotor cortices should be considered a nidus at the edge of multiple cortical networks which eventually become disrupted, causing failure of a widespread cortical connectome. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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16 pages, 2426 KiB  
Review
Lysosome Function and Dysfunction in Hereditary Spastic Paraplegias
by Daisy Edmison, Luyu Wang and Swetha Gowrishankar
Brain Sci. 2021, 11(2), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11020152 - 24 Jan 2021
Cited by 9 | Viewed by 3385
Abstract
Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the [...] Read more.
Hereditary Spastic Paraplegias (HSPs) are a genetically diverse group of inherited neurological diseases with over 80 associated gene loci. Over the last decade, research into mechanisms underlying HSPs has led to an emerging interest in lysosome dysfunction. In this review, we highlight the different classes of HSPs that have been linked to lysosome defects: (1) a subset of complex HSPs where mutations in lysosomal genes are causally linked to the diseases, (2) other complex HSPs where mutation in genes encoding membrane trafficking adaptors lead to lysosomal defects, and (3) a subset of HSPs where mutations affect genes encoding proteins whose function is primarily linked to a different cellular component or organelle such as microtubule severing and Endoplasmic Reticulum-shaping, while also altering to lysosomes. Interestingly, aberrant axonal lysosomes, associated with the latter two subsets of HSPs, are a key feature observed in other neurodegenerative diseases such as Alzheimer’s disease. We discuss how altered lysosome function and trafficking may be a critical contributor to HSP pathology and highlight the need for examining these features in the cortico-spinal motor neurons of HSP mutant models. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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10 pages, 19538 KiB  
Brief Report
Differential Epigenetic Signature of Corticospinal Motor Neurons in ALS
by Tunch Ozyurt and Mukesh Gautam
Brain Sci. 2021, 11(6), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci11060754 - 07 Jun 2021
Cited by 2 | Viewed by 2288
Abstract
Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is [...] Read more.
Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is pronounced cellular event in motor neurons diseases, such as amyotrophic lateral sclerosis (ALS). Genetic mutations contribute to only about ten percent of ALS. Thus understanding the involvement of other factors, such as epigenetic controls, is immensely valuable. Here, we investigated epigenomic signature of CSMN that become diseased due to misfolded SOD1 toxicity and TDP-43 pathology, by performing quantitative analysis of 5-methylcytosine (5mC) and 5-hydroxymethycytosine (5hmC) expression profiles during end-stage of the disease in hSOD1G93A, and prpTDP-43A315T mice. Our analysis revealed that expression of 5mC was specifically reduced in CSMN of both hSOD1G93A and prpTDP-43A315T mice. However, 5hmC expression was increased in the CSMN that becomes diseased due to misfolded SOD1 and decreased in CSMN that degenerates due to TDP-43 pathology. These results suggest the presence of a distinct difference between different underlying causes. These differential epigenetic events might modulate the expression profiles of select genes, and ultimately contribute to the different paths that lead to CSMN vulnerability in ALS. Full article
(This article belongs to the Special Issue Factors Responsible for CSMN Vulnerability)
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