Lecture 31: Amyotropic Lataeral Sclerosis Flashcards
Name 2 Disease that directly affect c_ell bodies_ of lower motoneurons (alpha and gamma)
- Poliomyelitis (polio)
- Acute, usually ‘__focal__’ degeneration of motoneurons resulting from viral (oral) infection
- Brought under control since the introduction of vaccination in the late 1950’s
Recent Phase I clinical study at Duke university: genetically modified polio virus for treatment of glioblastoma (brain cacner).
- Genetically modified virus injected into tumour by a neurosurgeon
- Virus can only replicate in cancer cells (oncolytic virus)
- Acts by triggering an immune response to cancer cells
- Syringomyelia
- Formation of large cysts within the central portion of the spinal cord
- Damage of ‘pain’ and ‘temperature’ fibres’ followed by damage of motoneuron cell bodies
- Pathogenesis unknown
What is Polio?
- Poliomyelitis (polio)
- Acute, usually ‘__focal__’ degeneration of motoneurons resulting from viral (oral) infection
- Brought under control since the introduction of vaccination in the late 1950’s
Recent Phase I clinical study at Duke university: genetically modified polio virus for treatment of glioblastoma (brain cacner).
- Genetically modified virus injected into tumour by a neurosurgeon
- Virus can only replicate in cancer cells (oncolytic virus)
- Acts by triggering an immune response to cancer cells
What is Amyotrophic lateral sclerosis?
‘Lou Gehrig’s disease’) (motoneuron disease – MND)
- Many neurological diseases cause weakness and wasting of skeletal muscles, and can lead to complete muscle paralysis. These disorders are usually associated with a lesion of parts of the brain outside the motor nuclei in the spinal cord and/or brainstem.
- In contrast, amyotrophic lateral sclerosis affects motoneurons themselves (as well as the upper motoneurons in the cerebral cortex; see below), and leads to very severe weakness of various groups of muscles.
Amyo = Lack of
Trophic = Maintanance and Growth
Amyotrophic = lack of maintanance and growth.
Sclerosis = Hard
(atrophy of muscles due to hardening of lateral spinal cord)
Describe the Symptoms of ALS
1) Progressive wasting, weakness and atrophy of muscles leading to paralysis
- Wasting and weakness of legs, arms and hands
- Difficulty with swallowing (dysphagia) and speech (dysarthria) (cf. ‘progressive bulbar palsy’)
- Impairment of respiration → pulmonary infection
2) Muscle stretch reflexes exaggerated and muscle tone increased
(‘spasticity’: painful, tight and stiff muscles)
What is the word for “difficulty swallowing”
swallowing (dysphagia)
What is the word for “Difficulty speaking”
speech (dysarthria)
What are some signs of ALS?
Signs of muscle denervation (Denervation: Loss of nerve supply):
- Fasciculations (visible twitches of some _motor units which survived atrophy (_temporarily enlarged and thus unstable); not painful but irritating)
- Fibrillations (spontaneous action potentials generated by individual muscle fibers only seen in EMG; not visible or felt)
No involvement of extraocular muscles (normal eye movements)
No involvement of anal and bladder sphincters
Usually no sensory or intellectual deficits
What are Fasiculations?
A sign of muscle denervation
Fasciculations (visible twitches of some motor units which survived atrophy (temporarily enlarged and thus unstable); not painful but irritating)
What are Fibrillations?
A sign of muscle denervation
Fibrillations (spontaneous action potentials generated by _individual muscle fiber_s only seen in EMG; not visible or felt)- even if they are ‘relaxed’
What are the causes of Amyotrophic Lateral Sclerosis symptoms?
Progressive degeneration of:
- ‘Lower’ motoneurons (muscle wasting/paralysis)
- motoneurons (α and ɣ) in the spinal cord; with exception of motoneurons controlling the sphincters
- m_otoneurons in the brain stem_; with exception of the Ill, IV and VI nuclei (eye movements)!
- ‘Upper’ motoneurons (corticospinal neurons in motor cortex)→increased ‘stretch’ reflexes +spasticity +Babinski reflex
Note the unusual combination of muscle wasting and increased stretch reflexes
What are some possible pathogenesis of Amyotrophic lateral Scelorsis?
Unknown.
- Autoimmune hypothesis: presence of antibodies against Ca2+ channels in some patients
- Neurotrophic hypothesis: ↓ levels of neurotrophic factors (eg. BDNF, NT3) which promote motoneuron survival
- Fas-induced cytotoxocity: increased sensitivity to activation of Fas (a member of ‘death receptor’ family) which increases expression of neuronal NOS (nitric oxide synthase), note that NO + •O2- → very toxic peroxynitrite
1. Oxidative stress hypothesis
- Damage of motoneurons by free radicals (reactive oxygen and nitrogen species such as •OH, •O2- and NO•), when radical
- production exceeds the detoxification capacity of specific enzymes (e.g. glutathione, superoxide dismutase, catalase)
- Note: mutation of antioxidant enzyme superoxide dismutase (SOD) in ~10% patients with familial form of ALS
- But… why does this only target certain motoneurons not others?
2. Excitotoxic hypothesis
Excessive activation of AMPA and/or NMDA receptors by glutamate (not glutamate itself)
Why?
- ↑ extracellular glutamate due to ↓ activity of glutamate transporter GLT1 (normal function is to transport glutamate) mainly in astrocytes surrounding motoneurons (surrounding astrocytes damaged by free radicals release from motoneurons?)
- ↓ expression of GluR2 subunit (normal function is to inhibit Ca2+ influx) of AMPA glutamate receptor
- Motoneurons which are typically involved in ALS have a lower abundance of GluR2 subunits in AMPA receptors
- This predisposes them to higher Ca2+ influxes and _excitotoxic da_mage.
- Note that AMPA receptors usually contain GluR2 subunits and therefore are not permeable to Ca2+.
But… why does this only target certain motoneurons not others?
3. TDP-43 / FUS mutation hypothesis (most recent findings):
- TDP-43 and FUS (proteins involved in RNA processing) are normally found in the nucleus
- The genes coding for these proteins mutate in some forms of familial ALS, and the two proteins are shifted to the cytoplasm where they form insoluble aggregates affecting neuronal function
All lower motor neurons degenerate in the Amyotrophic Lateral Sclerosis except for the…..
‘Lower’ motoneurons (muscle wasting/paralysis)
motoneurons (α and ɣ) in the spinal cord; with e_xception of motoneurons controlling the sphincters_
motoneurons in the brain stem; with e_xception of the Ill, IV and VI nuclei (eye movements)!_
Describe the Oxidative stress hypothesis of Amyotrophic Lateral Sclerosis
1. Oxidative stress hypothesis
- Damage of motoneurons by free radicals (reactive oxygen and nitrogen species such as •OH, •O2- and NO•), when radical
- production exceeds the detoxification capacity of specific enzymes (e.g. glutathione, superoxide dismutase, catalase)
- Note: mutation of antioxidant enzyme superoxide dismutase (SOD) in ~10% patients with familial form of ALS
- But… why does this only target certain motoneurons not others?
Describe the Excitotoxic hypothesis
- Excitotoxic hypothesis
Excessive activation of AMPA and/or NMDA receptors by glutamate (not glutamate itself)
Why?
- 1) ↑ extracellular glutamate due to ↓ activity of glutamate transporter GLT1 (normal function is to transport glutamate) mainly in astrocytes surrounding motoneurons (surrounding astrocytes damaged by free radicals release from motoneurons?)
- 2) ↓ expression of GluR2 subunit (normal function is to inhibit Ca2+ influx) of AMPA glutamate receptor
- Motoneurons which are typically involved in ALS have a lower abundance of GluR2 subunits in AMPA receptors
- This predisposes them to higher Ca2+ influxes and excitotoxic damage.
- Note that AMPA receptors usually contain GluR2 subunits and therefore are not permeable to Ca2+.
Describe the new hypothesis for the pathogensis of Amyotrophic Lateral Sclerosis
- TDP-43 / FUS mutation hypothesis (most recent findings):
- TDP-43 and FUS (proteins involved in RNA processing) are normally found in the nucleus
- The genes coding for these proteins mutate in some forms of familial ALS, and the two proteins are shifted to the cytoplasm where they form insoluble aggregates affecting neuronal function
