Lecture 12: ALS Flashcards
What is ALS?
Amyotrophic Lateral Sclerosis (ALS) isa progressive degenerative disease that affects neurons controlling voluntary muscles (AKA Lou Gherig’s disease)
Amyotrophic = no muscle nourishment
Lateral = location on spinal cord where sclerosis (scarring, hardening) occurs (lateral meaning outside portion of spinal cord)
– Steadily progressive;
– Evidence for slow vs. fast progressors; meaning there’s two different diseases happening but we don’t know enough so we categorize it all as one disease (ALS)
–Inherited vs. sporadic cases;
When do patients usually die after ALS diagnosis?
in 2-4 years
What are the clinical symptoms of ALS?
Loss of motor neuron function results in:
- Stiff muscles;
- Muscle twitching (spasms), often overlooked;
- Weakness due to decreased muscle size;
- Difficulty speaking, swallowing and eventually breathing (typically 1st symptoms to appear);
– if you don’t use your muscles, the body will stop nourishing them and keeping them alive. As you have death of those upper and lower motor neurons, you don’t get to activate and use the muscles resulting in muscle atrophy and degrade over time
Why is cognitive dysfunction less common in ALS?
- Cognitive dysfunction present in less than half of cases
- in parkinson’s and huntingtons, there’s more cognitive dysfunction cases because the person lives long enough for that degeneration of the motor system to pass to the cortex. In ALS, the person doesn’t usally live long enough for that degeneration to pass on to the cortex and also the degeneration is very specific to the upper and motor neurons which are very long so it takes time for the degeneration to pass on around
Where are motor neurons located and what are the two types?
– Cell bodies located in the motor cortex, brainstem or spinal cord.
– Axons (fibers) project to spinal cord or outside spinal cord to control organs, muscles and glands.
Two types:
1. Upper motor neuron (UMN): pyramidal cells that synapse onto interneurons in spinal cord and influence activity of LMN; the cell bodies of UMN resides in the motor cortex and the axons project to either the brain stem or spinal cord; Receive information from the neighbouring somatosensory cortex
- Lower motor neuron (LMN): efferent nerve fibers that carry signals from brainstem and spinal cord to muscle fibres; considered second order neurons because the UMN synapse with interneurons which then community to LMN; Innervated with striated muscles
What are the two types of receptors that ACh binds to?
- ACh binds to two types of receptors, and is responsible for muscle contractions
1. Nicotinic ACh receptors; ionotropic because they let in ions or out and it’s a very fast response
2. Muscarinic ACh receptors; metabotropic, so they are very slow acting
- ACh binds to two types of receptors, and is responsible for muscle contractions
What is the neuromuscular junction (NMJ)?
– point of contact with muscle is called a neuromuscular junction (NMJ)
– Motor neurons release acetyl choline (ACh) onto muscle tissue
– Many drugs and toxins target the NMJ (specifically the ACh receptors), and interfere with normal signaling:
Botulin Toxin;
Black Widow spider venom;
Nicotine;
Muscarine;
How does Botulin Toxin act on the cholinergic system?
– Botulin Toxin (aka Botox) is an extremely toxic compound produced by the bacteria Clostridium botulinum (Collection of protein sub-types: A –> G)
– These proteins are taken up selectively by peripheral cholinergic nerve terminals, including those located at the neuromuscular junction.
– Botox interferes with ACh release at nerve terminals, thereby blocking neurotransmission (prevents fusion of synaptic vesicles with nerve terminal membrane;
Results in muscle weakness or paralysis)
– Face wrinkles (e.g. crows feet, worry lines, frown lines, etc.) result in chronic contraction of specific facial muscles.
—> Botox can reduce these lines/wrinkles;
—> Each treatment is effective for a few months;
What is a motor unit?
Motor Unit = LMN cell body, axon and the multiple fibers it innervates
- An action potential will depolarize one motor unit’s muscle fibers nearly simultaneously.
- Multiple action potentials will overlay on each other;
- Action potentials can be additive, leading to a larger muscle contraction
Where does afferent sensory information travel towards?
– Afferent sensory information from somewhere in the periphery can:
1. Go directly towards CNS;
2. Or synapse with interneurons;
3. Or synapse with lower motor neurons (LMN); we know it can synapse directly with LMN because when you hit the patellar tendon in the knee it initiates motor movement so your leg jerks up automatically
sensory information goes up through the dorsal (top) root
Where does efferent motor information travel towards?
- Efferent motor commands, synapsing somewhere in spinal cord to LMN, controlling voluntary movement
- LMN can send its axons out to ventral root to make contact with muscle and cause contraction
How can you test certain reflexes?**
– Damage to the PNS often causes a decreased or absent reflex, as part of a LMN-type lesion
What causes ALS?
- Familial cases involve genetic mutations in superoxide dismutase (oxidative stress)
- –> Extremely long neurons, such as LMN, are susceptible to damage; Long axons have very long microtubules and other parts so if one little thing goes wrong it will get flagged for apoptosis. Long neurons also make it hard to repair something that goes wrong (things have to travel very far distances)
- –> Anything that happens along the axon will disrupt function of entire neuron;
- –> Disruptions in SOD1 function anywhere along a LMN causes dysfunctional cell
- Other causes are spinal muscular atrophy, other genetic causes, Polio, West Nile virus.
- No specific environmental factors have been identified
How do inclusion bodies/protein aggregates cause ALS?
- inclusion bodies in the cytoplasm of motor neurons; abnormal aggregations of protein
- Exactly which protein depends on the sub-type of ALS (e.g. sporadic vs. familial)
- SOD1 and TDP-43 proteins have been most studied protein aggregates.
- Aggregates lead to dysfunctional motor units.
- SOD is an enzyme that catalyzes the dismutation of the superoxide radical (O2-) into a less toxic/reactive chemical (e.g. O2 or H2O2).
- O2- is produced as a by-product of oxygen metabolism, and therefore regular cellular processes
- If not regulated, O2- can cause many types of cell damage.
- SOD is an important antioxidant defense in neurons.
- Mutations to SOD can lead to cell death because there is an imbalance in the productive and removal of the superoxide radical.
How can you screen for ALS?
- detailed history and conduct a neurological exam (including reflexes). Symptoms of muscle atrophy indicate LMN problem; Narrow down to PNS (weakness, atrophy) and refer to electromyogram (EMG) results
- Diagnosis is based on clinical features and EMG testing
