Weeks 1 - 4: Etiology and pathogenesis

Etiology of als

The etiology of ALS is multifactorial, involving genetic, environmental, and molecular factors1.

Most cases (90-95%) of ALS are sporadic (sALS) while the remaining 5-10% are familial (fALS), with clear genetic inheritance. Familial ALS is most commonly associated with mutations in SOD1, C9orf72, and TARDBP genes. Mutations in these genes are associated with protein aggregation, oxidative stress, and impaired RNA processing, contributing to motor neuron dysfunction (we will explore more about the genetic mechanisms of ALS later in the course)1. 

The etiology of sporadic ALS is less understood, but is believed to result from a combination of genetic susceptibility and environmental triggers. Risk factors such as exposure to neurotoxins, heavy metals, pesticides, and smoking have been implicated. Additionally, traumatic injuries and intense physical activity may increase the risk in some individuals. Research also suggests that dysregulation of cellular processes like mitochondrial function, axonal transport, and autophagy may play a role. Other risk factors include age and sex. The incidence of ALS increases after age 40 and is 1.5 times more likely to develop in those assigned male at birth1,2. 

Both familial and sporadic ALS are linked by common molecular mechanisms, including excitotoxicity due to excess glutamate, oxidative stress, and chronic inflammation. These processes converge to cause motor neuron death, which ultimately leads to the clinical manifestations of ALS1.

Despite advances in understanding ALS pathogenesis, the exact cause remains unclear, particularly in sporadic cases. This highlights the need for further research into the complex interactions between genetics, environmental exposures, and cellular pathways. Identifying these factors is crucial for developing effective therapies to slow or halt disease progression1,2.

pathogenesis of als

The pathogenesis of amyotrophic lateral sclerosis (ALS) involves complex molecular and cellular mechanisms that contribute to the progressive degeneration of motor neurons. Central to the disease is the disruption of neuronal homeostasis, driven by multiple converging pathways3.

One hallmark of ALS pathogenesis is the accumulation of misfolded and aggregated proteins in motor neurons. Mutations in several genes are linked to the formation of these toxic aggregates (we will explore more about the genetic mechanisms of ALS later in the course)3.

Mitochondrial dysfunction is another critical aspect of ALS. Motor neurons show signs of energy failure due to impaired oxidative phosphorylation and increased production of reactive oxygen species (ROS), which promote oxidative damage to cellular components such as DNA, lipids, and proteins3,4.

Dysfunction of axonal transport also contributes to motor neuron degeneration. Proper transport of organelles, nutrients, and signaling molecules along axons is essential for neuronal survival. In ALS, defects in microtubules and associated motor proteins impede this process, leading to neuronal stress and death3.

Neuroinflammation plays a significant role in disease progression. Microglia, astrocytes, and infiltrating immune cells release pro-inflammatory cytokines and neurotoxic substances that exacerbate motor neuron injury. These immune responses, initially protective, become maladaptive in ALS3,4.

Excitotoxicity, caused by excessive glutamate signaling, is another mechanism implicated in ALS. Dysfunction of the glutamate transporter EAAT2 in astrocytes leads to elevated synaptic glutamate, causing calcium overload and excitotoxic cell death in motor neurons3.

These interconnected processes—protein aggregation, mitochondrial dysfunction, axonal transport defects, neuroinflammation, and excitotoxicity—drive the loss of motor neurons in ALS. Understanding these pathways continues to guide the development of targeted therapies aimed at altering the disease course1,3.

Test your knowledge: etiology

Google Form Link

1. What percentage of ALS cases are familial (fALS)?

• A. 5-10%

• B. 20-30%

• C. 90-95%

• D. 50-60%

2.  Which of the following genes is NOT commonly associated with familial ALS?

• A. SOD1

• B. C9orf72

• C. TARDBP

• D. EAAT2

3. Which environmental factor has been implicated as a risk factor for sporadic ALS?

• A. High altitude

• B. Exposure to pesticides

• C. Cold climates

• D. High carbohydrate diet

4. At what age does the incidence of ALS typically increase?

• A. After age 20

• B. After age 40

• C. After age 60

• D. After age 75

5. Which sex is more likely to develop ALS?

• A. Female

• B. Male

• C. Equal likelihood

• D. No data available

6. What percentage of ALS cases are sporadic (sALS)?

• A. 5-10%

• B. 20-30%

• C. 50-60%

• D. 90-95%

7. Which of the following is NOT a proposed risk factor for sporadic ALS?

• A. Smoking

• B. Traumatic injuries

• C. Chronic dehydration

• D. Intense physical activity

8. Familial and sporadic ALS share which common molecular mechanism?

• A. Excess glutamate excitotoxicity

• B. Decreased protein aggregation

• C. Increased neurogenesis

• D. Enhanced synaptic repair

9. What is the primary challenge in identifying the cause of sporadic ALS?

• A. Lack of genetic studies

• B. Complexity of interactions between genes and environment

• C. Poor imaging technology

• D. Unreliable symptom reporting

10. Which of the following best describes the etiology of ALS?

• A. Single gene defect

• B. Multifactorial with genetic, environmental, and molecular components

• C. Purely environmental

• D. Autoimmune origin

Answer Key 

1. A. 5-10%

2. D. EAAT2

3. B. Exposure to pesticides

4. B. After age 40

5. B. Male

6. D. 90-95%

7. C. Chronic dehydration

8. A. Excess glutamate excitotoxicity

9. B. Complexity of interactions between genes and environment

10. B. Multifactorial with genetic, environmental, and molecular components

Test your knowledge: Pathogenesis

Google Form Link

1. Which of the following is a hallmark of ALS pathogenesis?

   • A. Enhanced synaptic growth

   • B. Protein misfolding and aggregation

   • C. Increased neurogenesis

   • D. Improved mitochondrial function

2. What type of dysfunction is associated with energy failure in ALS motor neurons?

   • A. Mitochondrial dysfunction

   • B. Synaptic overactivity

   • C. Excess protein synthesis

   • D. Hormonal imbalance

3. What is the role of microglia in ALS progression?

   • A. They repair damaged neurons.

   • B. They release neurotoxic substances.

   • C. They block inflammation.

   • D. They enhance muscle strength.

4. Which of the following is impaired, leading to excitotoxicity, in ALS?

   • A. SOD1 expression

   • B. TARDBP levels

   • C. EAAT2 glutamate transport

   • D. C9orf72 expansion

5. Which of these processes is NOT part of ALS pathogenesis?

   • A. Oxidative stress

   • B. Neuroinflammation

   • C. Enhanced cellular repair

   • D. Axonal transport defects

6. Protein aggregation in ALS is often linked to mutations in which gene?

   • A. TARDBP

   • B. BRCA1

   • C. EAAT2

   • D. CFTR

7. Which cellular component suffers from oxidative phosphorylation failure in ALS?

   • A. Nucleus

   • B. Ribosome

   • C. Mitochondria

   • D. Lysosome

8. Excitotoxicity in ALS primarily involves which neurotransmitter?

   • A. Dopamine

   • B. Serotonin

   • C. Glutamate

   • D. GABA

9. Axonal transport defects in ALS disrupt:

   • A. Synaptic vesicle release

   • B. Movement of organelles and nutrients

   • C. Blood-brain barrier function

   • D. DNA replication

10. Neuroinflammation in ALS involves which of the following cell types?

    • A. Microglia and astrocytes

    • B. Erythrocytes

    • C. Keratinocytes

    • D. Myocytes

Answer Key

1. B. Protein misfolding and aggregation

2. A. Mitochondrial dysfunction

3. B. They release neurotoxic substances

4. C. EAAT2 glutamate transport

5. C. Enhanced cellular repair

6. A. TARDBP

7. C. Mitochondria

8. C. Glutamate

9. B. Movement of organelles and nutrients

10. A. Microglia and astrocytes