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Amyotrophic Lateral Sclerosis Genetics - Current Situation On Mechanisms And Therapeutics


The scientific landscape around amyotrophic lateral sclerosis genetics is changing as the number of genes linked to disease risk and pathogenesis, as well as the cellular mechanisms involved, grows.

Amyotrophic lateral sclerosis (ALS) is a deadly motor neuron disease that causes degeneration of both upper and lower motor neurons.

The illness normally manifests as a persistently increasing muscular atrophy and weakening, with the effects on respiratory muscles limiting survival to 2-4 years following disease onset in most instances.

ALS is the most common adult motor neuron disease. It affects 2 out of every 100,000 people and is found in 5,4 out of every 100,000 people.

The two authorized drugs in general use, Riluzole and Edaravone, provide relatively small improvements and are only effective in certain people.

COPYRIGHT_SZ: Published on https://stationzilla.com/amyotrophic-lateral-sclerosis-genetics/ by Dr. Cooney Blades on 2022-07-24T08:30:15.882Z

Many things have slowed down the development of effective treatments for this deadly disease.

ALS is thought to have a large genetic component and a high heritability, but many of the gene changes that cause or make a person more likely to get ALS are not known.

The Genetics Of ALS

Clinical and basic research point to a variety of genetic causes of ALS.Up to 10% of ALS patients have a family member with the disease; these instances are inherited autosomally dominantly. The other 90–95% of ALS cases are sporadic, which means that no one in the family has ever had it.

Molecular genetic approaches are being used in ALS research. Genome-wide association studies and "next-generation" sequencing have added to "first-generation" methods like genetic linkage analysis to make it easier to find genes linked to ALS in large sample sets.

These breakthroughs have helped us understand the genetic etiology of fALS, with 40–55% of cases due to mutations in ALS-linked genes. Most disease-causing changes happen in SOD1, C9ORF72, FUS, and TARDBP, but disease-causing changes in other genes are rare.

2-Minute Neuroscience: Amyotrophic Lateral Sclerosis (ALS)

Missing Heritability In ALS

ALS lacks heredity owing to technical concerns and the disease's complexity (s). Limitations of big association study technology may contribute to ALS's lacking heritability.

Short-read, high-throughput sequencing is often used in ALS investigations. Single short-read platforms can identify single-nucleotide polymorphisms (SNPs) but not most structural variants (SVs) in the human genome.

Repetitive DNA amplification, short-read mapping, and SV detection methods make SVs challenging to examine, particularly those with large repetitions or in repetitive DNA regions.

Genome-wide association studies employ genotyping arrays that cover a million SNPs and involve thousands of patients. This technique has uncovered unique and rare ALS-linked genes, although heritable genetic features that contribute to ALS risk remain unknown.

The lack of heritability shows that SNPs probably don't make up a big part of ALS's genetic contribution. This shows how important it is to find other ways to study the cause of ALS, such as looking for genetic modifiers and risk factors.

ALS-Associated Genes

Superoxide Dismutase 1 Gene (SOD1)

In 1993, the SOD1 gene (encoding superoxide dismutase 1 [Cu/Zn]) was the first to be linked to ALS. One of three superoxide dismutase enzymes known in humans, SOD1, encodes a metalloenzyme of 153 amino acids. The protein binds copper and zinc, forming a very stable homodimer.

SOD1 dimers are found in the cytosol and the intermembranous region of mitochondria, where they catalyze the generation of oxygen and hydrogen peroxide from superoxide species generated during cellular respiration. A recent meta-analysis revealed that pathogenic SOD1 mutations account for around 15–30% of fALS and less than 2% of sALS cases.

TAR DNA-Binding Protein 43 (TDP-43)

Neuronal cytoplasmic ubiquitinated inclusions were found in most ALS spinal cord samples. In 2006, researchers discovered that TAR DNA-binding protein 43 (TDP-43) was the primary component of ubiquitinated protein aggregates in sALS patients.

Histological investigations have revealed that TDP-43 is present in the cytoplasmic aggregates of most ALS patients, including sporadic cases lacking TARDBP gene pathogenic mutations and those with C9ORF72 hexanucleotide repeat expansions. TDP-43 aggregation in ubiquitin-positive cytoplasmic neuronal inclusions is a pathogenic characteristic of ALS.

TDP-43 is a 414-amino-acid DNA/RNA-binding protein encoded by the TARDBP gene. TDP-43 has a nuclear localization signal and a nuclear export signal and shuttles between the nucleus and cytoplasm. TDP-43 is a gene expression regulator that controls the splicing of pre-mRNA, the stability of mRNA, its transport, its translation, and the control of non-coding RNA.

Fused In Sarcoma (FUS)

Pathogenic mutations in the gene encoding another RNA-binding protein, fused in sarcoma (FUS), were discovered in ALS patients in 2009. Juvenile and early-onset ALS are linked through FUS variants.

FUS-ALS is defined by pathological FUS aggregation, which has been observed to occur solely in individuals with pathogenic FUS gene variations. TDP-43 aggregation is rare in FUS-ALS patients, which shows that TDP-43 is not involved in the FUS disease path.

FUS encodes a 526 amino acid protein that is widely expressed and belongs to the FET family of RNA binding proteins. In normal physiological conditions, FUS is mostly found in the nucleus, but it goes to the cytoplasm to take part in transport between the nucleus and the cytoplasm.

C9ORF72 Gene

A hexanucleotide repeat expansion (GGGGCC) in the non-coding region of the C9ORF72 gene was found in 2011 as the most prevalent hereditary cause of ALS in European populations.

Typically, the gene has 5–10 copies of this hexanucleotide repeat expansion, but ALS individuals with the expansion may have hundreds to thousands of repetitions. In European populations, this hexanucleotide repeat expansion occurs in roughly 34% of fALS and 5% of sALS cases, but is less common in Asian groups.

The function of the C9ORF72 product is unknown, but recent investigations suggest that it regulates endosomal trafficking and autophagy. Several C9ORF72-deficient mouse models demonstrated immunological dysregulation, indicating a putative role for C9ORF72 in the immune system.

ALS: The Early Stages

Proposed Mechanisms Of Disease

Despite decades of investigation, sporadic ALS pathogens remain unidentified. Multiple variables likely contribute to the disease's formation and progression, not a single incident.

Genetic and phenotypic diversity amongst individuals makes it hard to determine ALS's pathogenic processes. Many disease pathways are proposed due to the high number of genes and cellular processes involved in ALS.

Disorders in RNA metabolism, protein homeostasis, nucleocytoplasmic transport, DNA repair, excitotoxicity, mitochondrial dysfunction, oxidative stress, axonal transport disruption, neuroinflammation, oligodendrocyte dysfunction, and vesicular transport abnormalities. When and how these processes contribute to disease etiology needs clarification.

Altered RNA Metabolism

The finding of disease-causing mutations in RNA-binding protein genes, TARDBP and FUS, shifted attention to RNA dysregulation as a critical pathomechanism in ALS.

RNA-binding proteins have a role in several areas of RNA metabolism, including splicing, transcription, transport, translation, and stress granule storage. EWS and TAF15 (both implicated in FTD), hnRNPA1, and MATR3 are among the RNA-binding proteins that are directly involved in neurodegeneration.

A number of RNA-binding factors have been discovered bound to the hexanucleotide repeat expansion in the C9ORF72 gene transcript. These findings have heightened interest in the function of RNA metabolism in neurodegenerative disorders.

Nucleocytoplasmic Transport Defects

The cytoplasmic mislocalization and nuclear depletion of RNA-binding proteins such as TDP-43 and FUS in ALS pathology imply that nuclear transport abnormalities play a role in ALS pathogenesis.

Recent research on the effects of C9ORF72 hexanucleotide repeat expansion has added to the mounting evidence of nucleocytoplasmic transport abnormalities in ALS.

In addition, 18 genetic moderators involved in nucleocytoplasmic transport and RNA export were discovered in a Drosophila genetic screen to uncover modifiers of C9ORF72 toxicity, emphasizing this system as a main target of hexanucleotide repeat expansion associated toxicity. See for a discussion of the importance of nucleocytoplasmic transport in ALS.

Impaired DNA Repair

Another proposed mechanism that may contribute to ALS development is impaired DNA repair. TDP-43 and FUS, two of the most well-studied ALS-related proteins, are involved in the prevention or repair of transcription-associated DNA damage.

FUS, in particular, seems to play a crucial role in this respect, since it is engaged in both homologous recombination and non-homologous end-joining repair pathways for double-stranded DNA breaks.

Variations in the genes of additional ALS-related RNA-binding proteins, including TAF15, SETX, and EWSR1, have also been associated with defective DNA damage repair, indicating that this pathway is disrupted in ALS etiology.

Approaches To Treatment


Multidisciplinary symptom management for ALS includes dietary and respiratory assistance. Most ALS patients use Riluzole. This medicine was licensed in 1995 and is only slightly effective, extending life by 2–3 months in certain patients and only in the first 6 months of treatment.

Riluzole was originally thought to modulate glutamatergic transmission. Riluzole's actions on glutamate receptors are limited, and its mechanism of action is likely more complicated. This may explain why Ceftriaxone, Memantine, and Talampanel failed ALS clinical trials.

Over 60 different compounds have been studied as ALS therapies since Riluzole's debut. Clinical studies involving anti-inflammatory, anti-oxidative, anti-glutamatergic, neuroprotective, and neurotrophic drugs dominate.

ALSFRS-R is the most popular main outcome metric for ALS therapy. Patients' gross motor, fine motor, bulbar, and respiratory function are evaluated on a 12-question questionnaire. Most of the substances that were tested in human clinical trials that looked at ALSFRS-R scores or how long people lived did not work.

In 2017, Japan, South Korea, and the U.S. authorized the first novel ALS therapy in two decades. Radicava (Edaravone) is a putative antioxidant chemical that reduces oxidative stress. Edaravone was licensed in Japan for cerebral embolism.

Two phase III clinical studies assessed Edaravone's efficacy for treating ALS by comparing ALSFRS-R scores to baseline. The first double-blind placebo-controlled study (MCI-186-16) found no differences between treatment and placebo groups.

A follow-up study (MCI-186-19) was conducted after a post hoc examination of the data. After 6 months of therapy, edaravone-treated individuals showed decreased functional loss compared to placebo-treated patients. This research permitted concomitant Riluzole. Most ALS therapies are tiny compounds. Alternative techniques, such as RNA-based therapies, have had less success.

Molecular Approaches To Treat ALS

Short interfering RNA (siRNA) and antisense oligonucleotides are two key RNA-targeted treatment methods (AOs). siRNA are double-stranded RNA molecules that engage with the RNA-induced silencing complex to silence target genes.

Several preclinical studies have targeted ALS genes using siRNA, but none have reached clinical trials. This study examines AO ALS therapies. Short, single-stranded AOs may bind to RNA via Watson-Crick base pairing and affect gene expression. They can be used to increase or decrease protein expression or to change the way protein isoforms are made.

Inefficient and poorly targeted distribution slows RNA analog medication therapy. Due to its size and negative charge, unmodified single-stranded RNA cannot pass through the cell membrane unassisted and is degraded quickly by nucleases.

Khvorova and Watts analyzed how chemical changes assisted with some of these concerns. Synthetic RNA-like medications are delivered to target cells via a nanoparticle delivery platform (typically a cationic polymer or lipid) or conjugation to a bioactive ligand or cell penetrating peptide.

Effective concentrations of AOs in the organ or tissue of interest may be difficult, although neurodegenerative illnesses can be treated with AOs by intrathecal injection. Neurons and glia quickly absorb AOs in the nervous system.

The blood-brain barrier inhibits dispersion into peripheral tissues and subsequent kidney and liver clearance, allowing for easier clinically effective concentrations. This allows for lesser dosages, reducing toxicity and off-target effects.

In addition to Eteplirsen (Exondys 51®) for Duchenne muscular dystrophy, Nusinersen (Spinraza®) for spinal muscular atrophy, and Inotersen (Tegsedi®) for inherited transthyretin-mediated amyloidosis, have obtained FDA clearance in recent years (hATTR). AO therapies are being explored for ALS.

A human body showing the inner part with a magnified part showing a nerve and a muscle
A human body showing the inner part with a magnified part showing a nerve and a muscle

Models For ALS

The difficulties in collecting live tissue or cells from patients' CNS has made determining the processes involved in ALS and other brain illnesses problematic.

Researchers have used a broad range of model systems to examine the intricate mechanisms that occur in this illness. In vitro biochemical systems, cell lines and primary cell cultures, and numerous small animal and rodent models are examples of these models. Patient-derived cellular models have recently been constructed and tested.

Rodent Models

Mice and rats contain almost all human genes. Drug evaluation in these animals boosts the likelihood of effective human translation over other animal models. The first SOD1 (G93A) and SOD1 (A4V) ALS animal models were created in 1994.

Translation from animal models to human clinical trials has been poor for medicinal uses. Rodents often have milder ALS characteristics than people, with some models exhibiting no neurodegeneration.

Rodents have a shorter life span than humans, so degenerative abnormalities emerge faster. The rodent's genetic background may also have confusing consequences. These variations in pathology and milder symptoms may restrict the value of mouse models in researching late-stage neurodegenerative illnesses.

Humans and rats have different RNA splicing and metabolism. Although constitutive exons are highly conserved across humans and rodents, barely a fourth of alternatively spliced exons are. This difference is important in ALS etiology, which is unknown. Humans and rats have different cellular, molecular, neuroanatomical, and circuitry functions.

Higher Mammal Models

Pigs and primates are being studied as potential ALS animal models. Pigs are used to imitate TDP-43 and SOD1-ALS because of their parallels to humans.

Transgenic pigs expressing TDP-43 M337V display an ALS-like phenotype with cytoplasmic mislocalization but no aggregates. Pigs with SOD1(G93A) had nuclear SOD1 accumulation, and TDP-43 and SOD1 models revealed protein interactions not found in rodent models.

Primate models illuminate disease pathophysiology. TDP-43 is mislocalized early in disease development in a TDP-43 overexpression model that mimics clinical ALS symptoms.

In this model, TDP-43 phosphorylation was only discovered in the latter stage of illness, and the hallmark 25-kDa C-terminal fragment was not detected, suggesting they may not be essential to trigger TDP-43-induced neuronal failure in monkeys. The TDP-43 location and cleavage differed between transgenic monkeys and mice expressing the M337V mutation. Contrary to the TDP-43 overexpression monkey model, C-terminal fragments were prevalent in this model.

Olfactory Stem Cell Cultures

Another patient-derived stem cell model that has recently arisen in the research of brain illnesses employs stem cells obtained from human patients' olfactory mucosa. The olfactory mucosa is a clinically accessible neural tissue that comprises various cell types, including a substantial population of multipotent neural stem cells.

These stem cells may be isolated from surrounding cells and enlarged as neurospheres (clusters of neural progenitor cells), which can then be propagated as neural progenitor cells in neurospheres or detached and propagated as olfactory neurosphere-derived stem cells (ONS cells). For future research, ONS cells may be differentiated into neurons or glia.

People Also Ask

Is Amyotrophic Lateral Sclerosis Curable?

Although there is currently no treatment for ALS, patients may be made more comfortable with the following options: the drugs are used to treat severe muscular cramps, excessive salivation, and other problems. To treat muscular cramps, use heat or whirlpool therapy.

What Vitamins Help Prevent Amyotrophic Lateral Sclerosis?

Vitamin D's antioxidant, anti-inflammatory, and possibly neuroprotective qualities have all been investigated. An early study at Harvard Medical School discovered that ALS patients who took at least 2,000 IU of Vitamin D daily had a slower drop in ALSFRS symptoms. Vitamin D may also help to slow down the course of ALS.

Do All Amyotrophic Lateral Sclerosis Patients Become Paralyzed?

Almost all voluntary muscles will become paralyzed as the illness advances to its ultimate stages. When the muscles in the mouth and throat become paralyzed, it becomes hard to communicate, eat, or drink regularly.

Does Exercise Help Amyotrophic Lateral Sclerosis Patients?

Exercise has been shown to help people with ALS feel less depressed and have more strength and stamina.


Many hurdles remain in understanding and treating amyotrophic lateral sclerosis. Unidentified heredity questions persist. Single nucleotide polymorphisms cause a proportion of ALS cases. Changes in how we look at genetic factors that affect disease, like copy number variations and structural polymorphisms, could help fill in the gaps.

Downstream consequences and putative causes loop back into each other, making amyotrophic lateral sclerosis genetically difficult to disentangle. It is not clear what role each proposed disease mechanism plays in the pathogenesis of amyotrophic lateral sclerosis or which are the first variables. This is because studies have shown different results depending on the protocols and model systems used.

Early and pre-symptomatic illness pathogenesis models may assist in distinguishing disease causes from effects. In most ALS genetics instances, TDP-43 is implicated in pathogenesis. When it becomes engaged in disease development is unknown, as is the significance of post-translational alterations to TDP-43 in ALS genetics. Amyotrophic lateral sclerosis protein aggregation's toxicity needs further study.

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About The Authors

Dr. Cooney Blades

Dr. Cooney Blades - I think the correct diagnosis is the most important factor.

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