Amyotrophic Lateral Sclerosis (ALS) is a motor neurone disease. Motor neurone (MND) diseases are a group of diseases which affect motor neurones in the Central and peripheral nervous system without any involvement of the sensory nervous system. MNDs can affect only upper motor neurones or only lower motor neurones or both simultaneously.

ALS is type of MND in which upper and lower motor neurone damage is seen simultaneously.

Pathogenesis vs Pathophysiology

It is important to understand that pathogenesis and pathophysiology are two different terms, even though they are used interchangeably. In ALS, however, it is important to make the distinction and understand it as well.

Pathogenesis is the mechanism that leads to the disease onset. These are the genetic, environmental and biochemical changes which lead to cell damage and set the ball rolling. If the disease was a raging fire, the pathogenetic mechanisms are the sparks. Pathogenesis of diseases are complicated and hard to isolate.

Pathophysiology, on the other hand, refers to the progress of the illness as the pathogenetic mechanisms remain unchecked. Pathophysiology is generally speaking easier to understand as we can usually observe it as it happens.

In ALS, the pathophysiology is reasonably understood while the pathogenesis is not. There are many pathogenetic mechanism which have been associated with ALS but no unifying theory has been established.

So to understand how ALS occurs fundamentally requires you to understand three levels of damage

1. Proposed pathogenetic mechanisms - what initiates the damage?

2. Pathophysiology - how the damage progresses?

3. Pathology - what is the damage that is ultimately caused?

Pathogenetic Mechanisms

ALS is seen in two forms - familial ALS (fALS) and sporadic ALS (sALS). Familial ALS accounts for about 10% of the cases. The pathogenetic mechanisms outlined here are seen in both forms of ALS.

1. Genetic mutations

   • Inherent instability of the mutant proteins → improper protein degradation ⇒ SOD 1 (Cytosolic enzyme superoxide dismutase), ubiquitin 1 and 2, p62

   • Mutant genes disturb RNA processing, transport and metabolism ⇒ C9orf72, TDP 43, FUS

     • C9orf72

       • there is an expansion of an intronic hexanucleotide repeat (-GGGGCC-)

       • C9orf72 ⇒ open reading frame 72 on chromosome 9 → 45-50 % cases have this mutation

     • TDP43 and FUS

       • multifunctional proteins which bind RNA and shuttle between nucleus and cytoplasm

       • TDP 43 ⇒ RNA binding protein encoded by the TAR DNA biding protein gene → 5% cases have this mutation

       • FUS / TLS ⇒ fused in sarcoma / translocated in liposarcoma → 5% cases have this mutation

   • Defective axonal cytoskeleton and transport → dynactin and profilin 1

2. Excitotoxicity

3. Defective Autophagy

4. Oxidative stress

5. Impairment of axonal transport

6. Mitochondrial dysfunction

Understand that the genetic mutations set the stage for the other pathogenetic processes to take place. Without them, the disease would not occur. Of the subsequent processes, research has shown that excitotoxicity is the most prevalent pathogenetic mechanism which leads to motor neurone damage in ALS.

Excitotoxicity

Excitotoxicity is the dominant hypothesis of ALS pathogenesis. Glutamate is the major excitatory neurotransmitter in mammalian CNS but in high concentrations, glutamate is toxic to neurones.

What happens when there is excessive glutamate?

• There is activation of glutamate receptors in neurons and glial cells (AMPA receptor)

• AMPA receptor triggers mitochondrial changes like

  • reduced O2 consumption

  • oxidative phosphorylation uncoupling

  • increased reactive oxygen species

• These pathways lead to loss of calcium buffer and poor energy management which can starve the cell and lead to apoptosis.

How is glutamate buildup normally prevented in neurones?

• Astrocytes take up the excess glutamate from the synaptic cleft via EAAT2 (astrocyte glutamate transporter excitatory amino acid-2)

• In some cases of ALS this transporter is damaged leading to excess glutamate in the cleft which subsequently leads to excitotoxicity.

Pathophysiological Mechanisms

Now we understand what happens to the neurones on a biochemical and genetic level. Next we need to understand the progress of the illness.

ALS is not the manifestation of a single disease process. It is a collection of a number of pathways which come together to cause the loss of motor neurones. It is important to recognise that the damage starts in one area of the motor neurone system and progresses to the other areas.

Theories proposed for the progress of ALS

1. Dying forward hypothesis - damage starts at the cortical level and degeneration is spread via a transsynaptic anterograde mechanism

2. Dying back hypothesis - dysfunction starts in the lower motor neurones and progresses to the upper motor neurones

3. Independent hypothesis - upper and lower motor neurones degenerate independent of each other

How do the motor neurones die?

The motor neurones die through Wallerian degeneration. The death of one neurone leads to axonal degeneration and death. Once the axon is degenerated, the dead cell is phagocitized by the surrounding Schwann cells. This can lead to formation of inclusion bodies which can be seen on biopsies.

This degeneration and death of motor neurones is seen extensively in the brain and the spinal cord. In the peripheral nervous system, the loss of axons leads to denervation of a motor unit. As a part of recovery, a nearby motor neurone may innervate the damaged area. The process of denervation and renervation is constant.

Why is it called Amyotrophic Lateral Sclerosis?

When the denervation exceeds the renervation process, clinical features manifest themselves. Progressive denervation leads to atrophy of the whole muscle causing amyotrophy.

As the damage extends to the cortical motor neurones, there is thinning of the corticospinal tracts. These tracts travel the lateral and anterior part of the spinal cord. Progressive loss of fibers leads to gliosis which makes the tracts firm which appears as lateral sclerosis on autopsy.

Pathology

We now know how the damage in ALS starts and how its spreads. What we still need to know is the end stage.

Muscle biopsies of ALS patients reveal atrophy of the muscles at various stages. Because of constant denervation and renervation, there is bunching of the viable muscle fibers in one area. As the disease progresses, there is widespread atrophy.

Nerve biopsies show inclusion bodies in ALS. There are many named inclusions, but here are a few:

1. Ubiquitylated inclusions - made up of ubiquitin, peripherin, dorfin

2. TAR DNA binding protein 43 (TDP-43)

3. Fused sarcoma proteins

4. Bunina bodies

5. Hyaline conglomerate inclusions

Which motor neurones are spared in ALS?

1. Occulomotor, trochlear and abducens nerve

2. Posterior columns

3. Clarke column - posterior column which recieves proprioceptive sensations from the thoracic spines - C8-L3/L4

4. Spinocerebellar tracts

5. Nucleus of onuf - controls the bowel and bladder function

Even if these are affected, they become involved much later in the disease.