Is Aging the only driving factor for Motor Neuron Disease?

Introduction

Aging Drives Neurodegeneration and Motor Neuron Disease Development

Effect of Lifestyle Behaviour on Motor Neuron Health

Effect of Family History on Motor Neuron Health

Conclusion

References

Authors:

Bhavya Matta (A0244852B)

Chen Wei Ling (A0242212Y)

Penny Wong Wenn Hwa (A0239685L)

Rachel Ng Jean Hwee (A0238423H)

Ryan Lee Ray Yen (A0234723J)

Introduction

In this blog we tackle the myth, Is aging the only risk factor involved in motor neuron degeneration? While aging is a significant factor, we explore the multifaceted aspects influencing neurodegenerative disorders. But first let us understand what are motor neurons and motor neuron diseases.

Labelled diagram of a Motor Unit

https://chadwaterbury.com/the-science-of-motor-unit-recruitment-part-1/

What are Motor Neurons?

We can think of motor neurons as messengers which carry signals from our brain to the muscles- allowing us to perform any action- from waving our hand to running a marathon!

The cell body of motor neurons is located in the motor cortex, brainstem or spinal cord. They transmit the signals from the brain and spinal cord to other effector organs, such as our muscles and glands. These signals, in the form of electrical impulses then generate muscle contraction.

Usually we describe muscle contractions using motor units. A motor unit consists of a single motor neuron and all its innervated muscle fibres.

Each motor neuron typically has around 50,000 synaptic inputs to these innervated muscle fibres. We can control the force generated during muscle contraction by varying the number of motor units transmitting the signal and the discharge rate of the action potentials of these motor units.

As we age, certain changes occur in the physiology of motor neurons, leading to a deterioration of their function. Age-related changes in the signals produced by the motor cortex and the physiology of motor units affect motor function and performance, leading to muscle weakness, decreased coordination and other impairment. Regular physical activity may modify some age-related changes in motor unit structure and function (Hunter et al., 2016).

Let’s talk about some of these changes in detail.

Aging and Motor Neurons

Ageing is associated with morphological, physiological and behavioral changes in motor neurons along with altered inputs from the peripheral and spinal centers. These changes include a rapid loss of motor units in people above 60 years, reduced amplitude of action potential, more variable motor unit discharge rates and altered synchronisation during muscle contractions. This translates to impairments in motor function such as reduced motor performance and also higher inconsistencies in older individuals while performing the same motor task repeatedly (Hunter et al.,2016).

Aged motor neurons show axonal atrophy, along with reduced expression of myelin and neurofilament genes. This could be due to a disruption or delay in the complex degeneration and regeneration process undergone by damaged axons in young adults. Moreover, ageing-associated chronic inflammation and increased oxidative stress further lead to axon injury, initiating degeneration (Manini et al.,2013).

Overview of the structural and physiological changes in the neuromuscular system in aging. (Hunter et al.,2016)

Table of Motor Neuron Diseases

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Motor Neuron Diseases

These are a group of diseases a group of neurological diseases that cause deterioration of the muscular system due to neuronal damage. Here we will focus on the most common MND, Amyotrophic lateral sclerosis. Other examples of MNDs include Alzheimer’s Disease, Spinal Muscular Atrophy (SMA).

Amyotrophic lateral sclerosis (ALS): causes the degeneration of upper and lower body (alpha) motor neurons. Usually beginning from the extremities, ALS causes muscle weakness and stiffness while also affecting muscle reflexes. It is driven by several molecular mechanisms such as:

Glutamate excitotoxicity: ALS patients show a progressive decrease in Glutamate receptors (GluR) in astrocytes leading to increased extracellular levels of glutamate. Accumulated glutamate is neurotoxic for synapses, and exacerbates GluR death due to overstimulation, leading to neuronal death via excitotoxicity.
Other molecular changes observed in motor neurons are increased oxidative stress, protein aggregation, mitochondrial dysfunction and impaired axonal transport.
While most cases of ALS are sporadic, about 10% of cases are familial (FALS) i.e have a genetic origin. Most of these cases show autosomal dominant inheritance patterns.

(Pilar et al.,2020).

Ageing and ALS: While current research has not established a direct correlation between aging and ALS, indirect mechanisms indicate aging as a risk factor for the disease. Several age-associated phenotypes of motor neurons such as decreased synaptic input in axons of alpha motor neurons, mitochondria dysfunction, and cytoplasmic accumulation of lipofuscin aggregates (which are rich in lipids, metals and misfolded proteins) play a role in mechanisms driving ALS (Pandya & Patani, 2020).

In the next section we further discuss the role of aging in driving motor neuron diseases.

The Hallmarks of Aging (López‐Otín et al., 2023)

Aging Drives Neurodegeneration and Motor Neuron Disease Development

Aging can be defined by 12 hallmarks (López‐Otín et al., 2023). These hallmarks describe the effects on the genetic, cellular and system level which are observed in the aging process. In this section, we seek to explore how the downstream effects of aging hallmarks lead to neurodegeneration, which can then result in MNDs.

In this section, we look at some research papers that highlight the different areas that aging impact, and how dysregulation or degeneration in these areas lead to neurodegeneration and MNDs.

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis (Herskovits et al., 2018)

A look into how SIRT1 dysregulation in aged cells will lead to downstream effects that drive neurodegeneration and promote NMJ denervation leading to ALS.

SIRT1 activity is vital in ensuring tight genetic control over expression of proteins involved in oxidative stress response, mitochondrial function and autophagy pathways. These are important pathways, which dysregulation lead to progressive degeneration of Neuromuscular Junctions (NMJ) that is a common presentation in ALS.

In aging cells, SIRT1 activity is reduced due to both the reduction of SIRT1 expression as well as the lower abundance of NAD+ which is a cofactor of the SIRT1 enzyme. As such, it is postulated that SIRT1 dysregulation is one of pathways through which aging drives development and progression of ALS.

Two concepts were explored in the paper. The first was the effect of SIRT1 expression on the structural integrity of the NMJ in aged mice and ALS mice. The second would be the genetic expression profiles between Aged and ALS mice to draw the conclusion on whether similar pathways are implicated in each.

Immunostaining to determine NMJ integrity

Labeling the presynaptic region of motor axons with an antibody against synaptotagmin‐2 (Syt2), a protein that associates with synaptic vesicles
Marking the postsynaptic region with fluorescently tagged alpha‐bungarotoxin, which binds with high affinity to muscle nicotinic acetylcholine receptors (AChRs).
Innervation was scored based on the overlap between pre‐ and postsynaptic regions.

Denervation, Partial Innervation, full innervation compared between WT and KO young mice (3-4 month old) (Herskovits et al., 2018)

There were no visible differences, indicating that KO of SIRT1 did not seem to cause any effects on NMJ in early life

Denervation, Partial Innervation, full innervation compared between WT and Tg (OE) young mice (3-4 month old) (Herskovits et al., 2018)

Also, similar trends were observed when comparing between WT and OE young mice.

Denervation, Partial Innervation, full innervation in old mice (18-24 month) compared between WT and KO. (Herskovits et al., 2018)

As compared to WT mice, there was a visible decrease in the quality of NMJ in KO mice, with higher denervation as compared to WT. This showcased reduction in expression or activity of SIRT1 would reduce NMJ quality

Denervation, Partial Innervation, full innervation in old mice (18-24 month) compared between WT and Tg (OE). (Herskovits et al., 2018)

On the other hand, when comparing between WT and OE aged mice. There were better NMJ quality in OE mice, with majority showing full innervation of NMJ. The comparison pointed to the OE of SIRT1 rescuing the decrease in NMJ denervation during old age.

RNA Seq to determine Transcriptomic profile in Normal Aging and ALS

90% upregulated pathways in aging also upregulated in ALS
Might point to the fact that the pathways implicated in aging do have the potential to drive progression into ALS

Heatmap of gene expression in young, aged and ALS mice (Herskovits et al., 2018)

Heatmap shows similar expression profiles of young, old, ALS.
Similar genes upregulated and downregulated in aging and ALS. Key difference is that the extent of upregulation and downregulation is of a greater magnitude in ALS

Comparison of upregulated and downregulated pathways of Old-Young and ALS-WT pairwise (Herskovits et al., 2018)

Inflammatory, Innate and Adaptive immune system upregulated in aging and ALS
Regulation of Synapse assembly, structure and activity downregulated in aging and ALS

Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (Marschallinger et al., 2020)

Aside from proteins, lipid accumulation in microglial cells also cause a change in the cell's behaviour which then leads to implications to function.

Microglia are the resident myeloid cells of the brain. Their continuous surveillance and regulated activation against pathological or damage-associated stimuli help maintain the health of the brain and integrity of motor neurons.

Multiple classifications of Microglia exist which help us understand the diverse functions that these immune cells play. One of the most common is the classification of M1 proinflammatory and M2 anti-inflammatory microglia. M1 microglia help to protect the brain against infection whereas M2 microglia promote recovery (Thompson & Tsirka, 2017).

In the aging brain, microglia experience loss of homeostatic molecular signatures, causing increased production of ROS and Inflammatory Cytokines; reduced phagocytic capacity of microglia also cause lysosomal deposit buildup (Marschallinger et al., 2020). Resulting from this, the brain suffers from inflammation and reduced recovery.

In this paper, the focus was on a particular subpopulation of microglia termed Lipid-droplet accumulating microglia (LDAM). LDAMs build up in the aging brain and showcase defects in phagocytosis and increased ROS and inflammatory cytokine production. This led the team to suspect that LDAM are part of the Neurodegenerative Microglia (MGnD) subset and contribute to neurodegeneration. Thus, generation of LDAM and the impacts of this phenotype on Microglia function was investigated.

Fluorescent microscopy reveals Lipid Droplets accumulation in Microglia of aged brain

BODIPY used to stain for lipid droplets and TMEM119 used to stain microglia.
The abundance of lipid droplets, number of lipid droplet containing cells and size of lipid droplets were being assessed in microglia cell population of young and aged brains.

Fluorescent images of BODIPY signifying lipid droplets (Marschallinger et al., 2020)

BODIPY stain revealed several lipid droplet in the hippocampi of aged mice brains.
BODIPY, TMEM119 and Hoechst stain merged image revealed that lipid droplets accumulated in microglial cell cytoplasm

Comparison of LD numbers in young and aged mice brain (Marschallinger et al., 2020)

Significantly greater number of lipid droplets per unit area in aged brain compared to young brain. Points to the accumulation of lipid droplets with age.

Comparison of abundance of lipid droplet containing microglia in young and aged mice brain (Marschallinger et al., 2020)

Greater percentage of BODIPY+, or lipid droplet containing microglia in aged brain. This points to the increased number of microglia in aged brain with impaired function, resulting in lipid accumulating phenotype.

Comparison of size of Lipid Droplet in young and aged mice brain (Marschallinger et al., 2020)

Larger average Lipid droplet size in aged brain as compared to young brain. Showing that the size of lipid droplet accumulated also increases with age. This might also suggest reduced ability of microglia to clear lipids.

RNA seq of LD-low and LD-high microglia reveals different transcriptomic profiles

Microglia were being being sorted into LD-low and LD-high groups based on their mean BODIPY flourescence intensity. This sorting was being done by flow cytometric analysis.
Subsequently, RNAseq was being carried out on these two subcategories of LD accumulating microglia

Volcano plot of differentially expressed genes in LD-low and LD-high microglia (Marschallinger et al., 2020)

Volcano plot representing the differentially expressed genes in LD-low and LD-high genes derived from RNAseq.
Genes in red are those involved in phagosome maturation
Genes in purple are those involved in ROS production
This hints to the fact that there might be differences in the phagocytic capability and amount or speed of ROS produced when comparing between LD-low and LD-high microglia

Investigation of upstream regulators of 200 genes that are differentially expressed in LD-low and LD-high microglia
LPS is the top upstream regulator of the differentially expressed genes, pointing to inflammation as the possible main cause of lipid accumulation in microglia

Upstream regulators of differentially expressed genes in LD-low and LD-high microglia (Marschallinger et al., 2020)

Gene overlap between LG-high and microglia in aging and diseased conditions (Marschallinger et al., 2020)

Genes upregulated or downregulated in microglia during aging, Alzheimer Disease (AD), Amylotrophic Lateral Sclerosis (ALS), Damage Associated Microglia (DAM) and MGnD compared with gene expression profile of LD-high microglia.
There were some overlaps between the upregulated and downregulated genes. However, there were a great number of contrasts, whereby genes upregulated in LD-high microglia were downregluated in aging and diseased associated microglia, and vice versa.
As such, the correlation between LD-high microglia and aging as well as other neurodegenerative disease states could not be clearly determined.

LPS Stimulation of Lipid Droplet Accumulation

Since LPS was identified as the top upstream regulator of differential gene expression between LD-high and LD-low microglia, the team used LPS stimulation to investigate if the accumulation of lipid droplets were due to inflammatory stimulation
Triacsin C was used to inhibit de-novo synthesis of glycerolipids, preventing lipid droplet formation (Marschallinger et al., 2020). It was used to prove that any lipid droplets formed was due to synthesis and accumulation of lipids in response to LPS stimuli.

Fluorescence microscopy and quantification of BODIPY+ cells under different conditions. Followed by quantification of mean fluorescence index of the cell population (Marschallinger et al., 2020)

Stimulation with LPS caused a significant increase in the number of LD-containing microglia, signifying that inflammatory stimulus was indeed an initiator of LDAM formation
Treatment with LPS and Triacsin C caused the number of LD-containing microglia to resemble that of non-stimulated conditions.
Taken together, it can be concluded that inflammatory stimuli in the aging brain results in formation of LDAMs.

Lipid Accumulation in Microglia reduces its phagocytotic capacity

LDAM generated by stimulating BV2 cells with LPS were being exposed to zymosan particles derivatized with pHrodo (Marschallinger et al., 2020). Phagocytotic uptake of zymosan was then being quantified using fluorescence microscopy
Myelin debris was being injected into aged mice brain and the phagocytotic capacity of aged mice BODIPY+ and BODIPY- microglia cells were also compared

Fluorescence microscopy of BODIPY and Zymosan-pHRodo and quantification (Marschallinger et al., 2020)

Fluorescent microscopy reveals that BODIPY+ cells are often Zymosan-, indicating that LDAMs have limited capacity to phagocytose zymosan as compared to normal microglia.
Quantification of flourescent tagged cells shows differential ability of BODIPY+ and BODIPY- cells to phagocytose Zymosan, where BODIPY+ LDAMs had a significantly lower phagocytic activity than BODIPY- normal microglia.
This shows that accumulation of lipid droplets in microglia has a negative impact on phagocytic ability of the cells, hence reducing their capacity to play a protective role in the brain.

Experiment graphical representation, fluorescence microscopy of BODIPY and Myelin 555 and quantification (Marschallinger et al., 2020)

Similarly, using aged mice and injecting myelin to the brain, BODIPY+ LDAMs had a significantly lower ability than BODIPY- microglia in phagocytosis of myelin debris.
This indicates the reduced ability of LDAM to clear cellular debris and upkeep a healthy cellular environment in the brain.

Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans (Castro et al., 2023)

Labeled diagram of a motor neuron. In Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Anatomy_and_physiology_of_animals_Motor_neuron.jpg

Spinal motor neurons are the largest neurons in the spinal cord and are essential for voluntary movement. They possess extensive dendritic arbors and long axons that connect with skeletal muscle fibers.

Spinal motor neurons form excitatory (glutamatergic and cholinergic) and inhibitory (GABAergic and glycinergic) synapses along their dendritic arbor and soma, which are responsible for executing fine and complex motor commands – together referred to as the motor circuitry (Castro et al., 2023). Once activated, motor neurons release neurotransmitters from their axon terminals at neuromuscular junctions to trigger muscle contraction (Rodríguez et al., 2020).

Defects in spinal motor neurons have been associated with motor function decline during aging. In this paper, it was found that motor neurons do not die in aged female and male mice, rhesus monkeys, and humans (Castro et al., 2023). Rather, they undergo a selective and progressive shedding of excitatory synaptic inputs throughout the soma and dendritic arbor with aging that contribute to motor deficits.

Normal ageing bears a variety of structural and functional consequences for motor neurons such as in the loss of synaptic inputs, which eventually could directly or indirectly contribute to motor neuron pathology in motor neuron diseases like ALS (Pandya & Patani, 2020).

Numbers of excitatory synaptic puncta on motor neuron soma, dendrites and ventral horn decrease in aged mice

Lumbar spinal cord sections from young and aged mice were used to examine synaptic inputs along the entire surface of the soma and over an average distance of 302 μm of the dendritic arbor
Imaging was done on stitched, tile scan, Z stack confocal images of lumbar spinal cord coronal sections (Castro et al., 2023)

Quantification of excitatory and inhibitory inputs on spinal motor neurons in lumbar spinal cord samples extracted from aged and young mice (Castro et al., 2023)

A decrease in excitatory synaptic density (VGluT1, VGluT2 and VAChT) was observed in ageing mice by as early as 12 months of age
In contrast, inhibitory synaptic density (Gad67 and GlyT2) remain relatively unchanged, with an increase seen in the dendrite regions for Gad67

Fluorescence microscopy images of excitatory and inhibitory inputs on spinal motor neurons in lumbar spinal cord samples extracted from aged and young mice (Castro et al., 2023)

The mice motor neurons are labeled by tdTomato and fluoresce red. VGLuT1 excitatory synapses fluoresce green and Gad67 inhibitory synapses fluoresce fuschia.

Loss of excitatory synapses (green) is seen in motor neurons mouse lumbar spinal cords in aged vs young mice
Negligible change in inhibitory synapses (fuschia) is seen with ageing

Motor neuron synaptic coverage is lost in ageing mice

Lumbar spinal cord sections from young and aged mice were viewed under electron microscopy

Electron microscope images of young and aged motor neurons in mice lumbar spinal cords (Castro et al., 2023)

Motor neuron soma and proximal dendrites (green) and presynaptic boutons (magenta). Presynaptic boutons/terminals on motor neuron dendrites are sites where motor neurons receive signals.

EM imaging of motor neuron synaptic coverage shows a significant reduction in synaptic coverage of proximal dendrites in aged mice (4 months vs 28 months of age)
The loss of motor neuron synaptic coverage of proximal dendrites is influenced by a reduction in density and size of synaptic boutons (Castro et al., 2023)
Synaptic loss is known to be a major pathological feature of neurodegenerative diseases including ALS (Gelon et al., 2022)
Presynaptic densities around the soma and proximal dendrites of lower motor neurons have been seen to be significantly decreased in ALS spinal cord tissues (Gelon et al., 2022)

‘Presynaptic Terminal’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License.

The loss of presynaptic boutons/terminals decreases the ability of motor neurons to relay signals to exert movements in muscles.

There are no significant changes in human motor neuron density & soma size with ageing, but excitatory synaptic inputs on motor neurons decrease.

Cervical spinal cord tissue isolated from young and aged subjects with non-diseased clinical brain diagnosis was used to examine motor neuron density and inhibitory and excitatory synapse density.

Quantification of motor neuron and synaptic densities in young vs old human cervical spinal cord tissue samples (Castro et al., 2023)

Fluorescence microscopy images of motor neuron and synaptic densities in young vs old human cervical spinal cord tissue samples (Castro et al., 2023)

Images of motor neurons (NeuN, red), glutamatergic synapses (VGluT1, green) and GABAergic synapses (VGAT, fuchsia) of young and aged humans.

No significant changes in motor neuron density and soma size were found
A significant decrease in VGluT1 excitatory synapses in both the soma and ventral horn were observed in comparing aged and young spinal cord tissue, while VGAT inhibitory synapses remained largely unchanged
Excitatory synaptic dysfunction has been found to be a major feature of spinal muscular atrophy (Fletcher et al., 2017)

The loss of excitatory synapses and maintenance of inhibitory synapses in various regions of spinal motor neurons causes synaptic dysfunctions. The higher threshold to activate motor neurons due to the increased proportion of inhibitory synapses may result in fewer motor units in old age (Hepple & Rice, 2015), leading to a reduction in the number of muscle fibers that can be recruited to perform a particular motor task. Downstream, the initiation and coordination of movements can also be impacted (Castro et al., 2023). Synaptic dysfunctions and the reduction of excitatory synapses are also major pathogenic events in in spinal muscular atrophy (Simon et al., 2020) and ALS (Gelon et al., 2022), among other neurodegenerative diseases. The mechanisms that occur in parallel between normal aging in motor neurons and motor neuron diseases, as well is an area that currently lacks research focus, given that age-related deficits in motor neuron function seem to be prerequisite to the development of motor neuron diseases such as ALS (Pandya & Patani, 2020)

Several genes that are differentially expressed in aged motor neurons are shared with ALS and axotomized motor neuron models

RNA-Seq by GeneWiz was performed on immunoprecipitated ribosome-mRNA complexes of aging motor neurons from mice before reverse transcription and quantitative real-time polymerase chain reaction (qPCR).

Comparison of differentially expressed genes and activated canonical pathways across aged, axotomized and ALS model mice motor neurons (Castro et al., 2023)

Axotomy refers to the severing of axons on the motor neurons, a form of motor neuron degeneration. Axotomy is often present in many neurodegenerative disorders. SOD1G93A motor neurons are ALS-diseased motor neurons.

102 genes were found to be uniquely upregulated in aged motor neurons. In addition to a number of genes that are shared between the three conditions (aged, ALS and axotomized), 7 are shared among all 3 conditions, including C1qa, Cd63, Npy, Serpinb1a, Sprr1a, Tyrobp, and Vim (Castro et al., 2023)
While aged motor neurons do have their own set of unique DEGs, they share certain genes and pathways with diseased motor neurons (degenerated and ALS models), demonstrating that aged motor neurons are under significant stress (Castro et al., 2023), and drawing a strong connection between aging and motor neuron diseases.

Effect of Lifestyle Behaviour on Motor Neuron Health

While getting older might be an important factor affecting motor neuron degeneration, certain lifestyle habits also have an impact on the health of motor neurons. In an experiment carried out by Western Michigan University, researchers sought to find out if there was a correlation between long-term exercise and structural plasticity of motor neurons. Structural plasticity of motor neurons refers to their ability to respond to changes in the environment, resulting in a change in their phenotypes (without any effect on their genetic material) (Shen S et al, 2020).

Prior to the introduction of voluntary exercise into the experimental set up, the cell body size of motor neurons were measured in rats of different ages. The results showed that rats from adult (12 and 18 months old) and old (24 months old) age groups had the greatest decline in cell size distributions. The researchers theorised that this large decline might be due to the loss of large motor neuron groups, which control movements requiring high force or ballistic movements. It could be concluded that the cell body size of motor neurons decreases with increased age.

To track the effect of long term exercise on motor neurons, two groups of rats were used – sedentary-aged rats and age-matched exercised rats. Sedentary rats were kept in cages with limited space with no running wheel. For exercised rats, long-term exercise was introduced at different time points in different groups of rats. For young rats , the duration of exercise was 10 weeks from 1 to 3 months of age. For adult and old rats, the duration of exercise was 6 months, from 6 to 12 months of age, 12 to 18 months of age and 18 to 24 months of age.

From Cintrón-Colón, A. F. (2022)

In conclusion, at any age, long-term exercise seems to help to improve the maintenance and restoration of motor neurons. Initiating long-term exercise at an older age seems to result in the greatest extent of improvement, as compared to other ages.

Effect of Family History on Motor Neuron Health

Apart from lifestyle behaviours, there is also evidence suggesting that family history does play a role in the development of motor neuron diseases as well. This finding was found in a cohort study carried out in Sweden, in which specific groups of people related to probands in their families were followed up for their amyotrophic lateral sclerosis (ALS) diagnosis. A proband is defined as the first person in the family to be diagnosed with ALS (Fang et al., 2009).

In this study, three groups of people were involved: full siblings (1909), children (13947), and spouses (5405). Each group was being compared to another group not related to probands to determine the incidence of ALS. After which, the risk ratio, 95% confidence interval of having ALS, and ratio of ALS incidence rates were calculated using the Poisson regression model.

Upon analysis, it was found that full siblings and children are approximately 17 times and 9 times more likely to be diagnosed with ALS when associated with probands compared to non-probands. This suggests that family history does contribute substantially to the incidence of ALS in people, especially in these groups. Furthermore, there is an inverse relationship between incidence rate and relative risk of ALS when taking into account the age when people were being followed up. This also shows the impact of family history on the overall aspect occurrence of ALS.

Analysis of risk of developing ALS in full siblings and children in exposure group compared to reference group in Sweden, 1961-2005 (Fang et al., 2009)

Analysis of incidence rates (IRs per 100,000 person-years) and relative risks (RRs) of exposure group compared to reference group, with follow-up at different ages (Fang et al., 2009)

Legend:

Grey dashed line with circles: IR of reference group
Black dashed line with circles: IR of exposed group
Solid black line with squares: RR

Scaling out from the commonly-associated ALS, further research has been done to identify the genetic basis behind motor neuron diseases with influence from family history. In a sequencing study carried out on another population in Sweden, five genes were being compared for their extent of variation and their impact towards the development of motor neuron diseases (Black et al., 2017).

For a start, it was hypothesised that accumulation of mutations in these genes can lead to the occurrence of familial ALS cases. Recent evidence has shown that such occurrence can reach as high as 70% of known cases, which suggests the underlying importance of investigating the effects of such genes.

In this study, a total of 441 individuals with different types of motor neuron diseases were recruited, of which there were three pairs with a certain level of familial relation. For each individual, five genes (namely: SOD1, TARDBP, OPTN, TBK1, NEK1) had their exons amplified and subsequently sequenced. Three types of variants (stop-gain, frameshift, splice site) with an effect on proteins linked to incidence of motor neuron diseases were specifically investigated.

Upon analysis, it was found that 44 out of 429 individuals with recorded family history can trace back past motor neuron disease cases in their families. When comparing between the genetic variation and the phenotypic effect, it is clear that such variations as listed above are correlated with familial history of the disease, earlier incidence of disease, and higher probability of incidence in females. In addition, variations in different genes also show different survival rates, of which having variation in both TBK1 and NEK1 genes lead to fastest deaths. This suggests that gene mutations are being triggered by family history of motor neuron diseases, which can greatly decrease the lifespan of individuals.

Analysis of motor neuron disease development in individuals with the use of different statistical tests to account for the genetic variations (Black et al., 2017)

Kaplan-Meier graph of cumulative probability of survival against survival from onset, taking into account different genetic variations (Black et al., 2017)

Legend:

Nil: Absence of particular genetic variation
C9orf72: Presence of pathogenic expansion
SOD1: Presence of genetic variation in SOD1 gene
Other: Presence of genetic variation in TARDBP/OPTN/TBK1/NEK1 gene
Digenic: Presence of genetic variation in two particular genes

All in all, family history is also an important contributing factor towards motor neuron health.

Conclusion

Aging brings about significant changes in the physiological and structural makeup of motor neurons, including the loss of motor units, diminished synaptic input, and axonal atrophy. These changes result in a decline in motor function and consistency. The age-related characteristics of motor neurons also play a crucial role in the mechanisms underlying motor neuron diseases like ALS. But aging is definitely not the only factor that affects motor neuon degeneration (MND).

Normal ageing bears a variety of structural and functional consequences for motor neurons. SIRT1 dysregulation, buildup of lipid-droplet accumulating microglia, and synaptic dysfunctions that emerge in aged motor neurons all eventually could directly or indirectly contribute to motor neuron pathology in motor neuron diseases. Age-related changes in the CNS and Motor Neurons may heavily influence the development of neurodegenerative diseases involving motor neurons, such as ALS. An integration of ageing and motor neuron disease research that takes into consideration the parallels between the two can allow for better mechanistic insight and therapeutic advancement (Pandya & Patani, 2020) to find novel therapy options for these highly debilitating and fatal diseases.

One's family history can also determine the likelyhood of developing neuron diseases. The presence of positive cases of motor neuron diseases along one's family tree can lead to continued persistence of such neuron diseases in offspring and relatives. This factor of family history can lead to mutation on a particular gene that is associated with these diseases, thus having an impact on differential survival rates. Certain lifestyle behaviours can also play a part in the health of one's motor neurons. Unfortunately, long term exercise cannot completely eradicate degeneration of motor neurons. However, the research shown in this blog suggests that integrating exercise into one's lifestyle, especially at older age, can help to maintain and restore motor neurons.

While there are various treatments out there, according to MNDA, the only treatment of MND currently approved in the UK, is riluzole, a small molecule inhibitor of glutamate release from neurons in the brain (Doble, 1996). The drug works on the basis of the excitotoxic cell death hypothesis of neurodegeneration, where intense exposure of neurons to glutamate or other excitatory amino acids results in cell death (Choi, 1992). However, there is a lack of therapy options that use aging as the target to reduce degradation or prevent motor neuron degeneration. Though alternative therapies exist, including stem cell therapies and supplements or diets, their efficacy, safety and mechanism of action have yet to be ascertained (Motor Neurone Disease Association, 2021). As such, it might be interesting to look towards aging and its hallmarks to identify suitable targets that have direct and significant implications of MNDs.

References

Black, H. A., Leighton, D. J., Cleary, E. M., Rose, E., Stephenson, L., Colville, S., Ross, D., Warner, J., Porteous, M., Gorrie, G. H., Swingler, R., Goldstein, D., Harms, M. B., Connick, P., Pal, S., Aitman, T. J., & Chandran, S. (2017). Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiology of Aging, 51, 178.e11-178.e20. https://doi.org/10.1016/j.neurobiolaging.2016.12.013

Castro, R., Lopes, M., Settlage, R. E., & Valdez, G. (2023). Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans. JCI Insight, 8(9). https://doi.org/10.1172/jci.insight.168448

Choi, D. W. (1992). Excitotoxic cell death. Journal of Neurobiology, 23(9), 1261–1276. https://doi.org/10.1002/neu.480230915

Cintrón-Colón, A. F. (2022). From Young to Old: The Effects of Sedentary-Aging and Exercise Interventions on Structural Plasticity of Lumbar Motor Neurons, NMJ, and Glial Cell Line-Derived Neurotrophic Factor Expression. Western Michigan University.

Doble, A. (1996). The pharmacology and mechanism of action of riluzole. Neurology, 47(Issue 6, Supplement 4), 233S-241S. https://doi.org/10.1212/wnl.47.6_suppl_4.233s

Fang, F., Kamel, F., Lichtenstein, P., Bellocco, R., Sparén, P., Sandler, D. P., & Ye, W. (2009). Familial aggregation of amyotrophic lateral sclerosis. Annals of Neurology, 66(1), 94–99. https://doi.org/10.1002/ana.21580

Fletcher, E. V., Simon, C. M., Pagiazitis, J. G., Chalif, J. I., Aleksandra Vukojicic, Drobac, E., Wang, X., & Mentis, G. Z. (2017). Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy. Nature Neuroscience, 20(7), 905–916. https://doi.org/10.1038/nn.4561

Gelon, P. A., Dutchak, P. A., & Sephton, C. F. (2022). Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease. Frontiers in Molecular Neuroscience, 15. https://doi.org/10.3389/fnmol.2022.1000183

Hepple, R. T., & Rice, C. L. (2015). Innervation and neuromuscular control in ageing skeletal muscle. The Journal of Physiology, 594(8), 1965–1978. https://doi.org/10.1113/jp270561

Herskovits, A. Z., Hunter, T. N., Maxwell, N., Pereira, K., Whittaker, C. A., Valdez, G., & Guarente, L. (2018). SIRT1 deacetylase in aging-induced neuromuscular degeneration and amyotrophic lateral sclerosis. Aging Cell, 17(6), e12839. https://doi.org/10.1111/acel.12839

Hunter, S. K., Pereira, H. M., & Keenan, K. G. (2016). The aging neuromuscular system and motor performance. Journal of applied physiology (Bethesda, Md. : 1985), 121(4), 982–995. https://doi.org/10.1152/japplphysiol.00475.2016

Lawson, R. (2007). Labeled diagram of a motor neuron. In Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Anatomy_and_physiology_of_animals_Motor_neuron.jpg

López‐Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. https://doi.org/10.1016/j.cell.2022.11.001

Manini, T. M., Hong, S. L., & Clark, B. C. (2013). Aging and muscle: a neuron's perspective. Current opinion in clinical nutrition and metabolic care, 16(1), 21–26. https://doi.org/10.1097/MCO.0b013e32835b5880

Marschallinger, J., Iram, T., Zardeneta, M. E., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., Kim, J., Tevini, J., Felder, T. K., Wolinski, H., Bertozzi, C. R., Bassik, M. C., Aigner, L., & Wyss‐Coray, T. (2020). Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature Neuroscience, 23(2), 194–208. https://doi.org/10.1038/s41593-019-0566-1

Motor Neurone Disease Association. (2021). Unproven treatments in MND Information Sheet C. MNDA.

Pandya, V. A., & Patani, R. (2020). Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective. Brain : a journal of neurology, 143(4), 1057–1072. https://doi.org/10.1093/brain/awz360

Rodríguez, P. M., Cossins, J., Beeson, D., & Vincent, A. (2020). The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis. Frontiers in Molecular Neuroscience, 13. https://doi.org/10.3389/fnmol.2020.610964

Rojas, P., Ramírez, A. I., Fernández-Albarral, J. A., López-Cuenca, I., Salobrar-García, E., Cadena, M., Elvira-Hurtado, L., Salazar, J. J., de Hoz, R., & Ramírez, J. M. (2020). Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease With Ocular Involvement. Frontiers in neuroscience, 14, 566858. https://doi.org/10.3389/fnins.2020.566858

Shen S, Clairambault J. (2020). Cell plasticity in cancer cell populations. F1000Res. 22;9:F1000 Faculty Rev-635. doi: 10.12688/f1000research.24803.1. PMID: 32595946; PMCID: PMC7309415.

Simon, C. M., Blanco-Redondo, B., Buettner, J. M., Pagiazitis, J. G., Fletcher, E. V., Sime, K., & Mentis, G. Z. (2020). Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice. The Journal of Neuroscience, 41(2), 376–389. https://doi.org/10.1523/jneurosci.2142-20.2020

Thompson, K. K., & Tsirka, S. E. (2017). The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity. International journal of molecular sciences, 18(3), 504. https://doi.org/10.3390/ijms18030504

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