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漸凍症amyotrophic lateral sclerosis
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Lou Gehrig's disease
19319399
Jean-Martin Charcot
Amyotrophic lateral sclerosis (ALS)Amyotrophic lateral sclerosis (ALS)
(Rosen DR et al. Nature 1993)
18691869
2
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ALS: Epidemiology
• ALS is the most common form of motor neuron disease.
• Sporadic forms (unknown cause) account for about 90-95 percent of ALS cases.
• Familial forms (AD inherited disease) make up approximately 5-10 percent.
• Slight male predominance for sporadic ALS.
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ALS: Epidemiology• The incidence of ALS increases with each decade,
especially after age 40 years.• Peak age of onset is 50-70’s.• The only established risk factors for ALS are age and
family history. • Increased risk for developing ALS has been suggested
for laborers engaged in agricultural work, factory work, heavy manual labor, exposure to welding or soldering, and work in the plastics industry.
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ALS: Clinical Features
• The clinical hallmark of ALS is the combination of upper motor neuron and lower motor neuron signs.
• UMN signs include hyperreflexia, spasticity, extensor plantar response (up going toes), and positive jaw jerk.
• LMN signs include weakness, muscle atrophy, cramps and fasciculations.
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causing progressive muscular atrophy
loss of motor neurons in the spinal cord, brainstem and motor cortex
patients die due to respiratory failure caused by bronchial muscular dystrophy in 3-5 years
lose the ability to initiate and control all voluntary movement
(John M et al. PNAS 2010)8
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ALS: Clinical Features
• The loss of motor neurons results in the primary clinical symptoms and signs ALS. These may produce impairment affecting limb, bulbar, axial and respiratory function.
• Differences in site of onset, pattern and speed of spread, and the degree of upper motor neuron (UMN) and/or lower motor neuron (LMN) dysfunction produce a disorder that is remarkably variable between individuals.
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neuroinflammation
glutamate excitotoxicity
altered cytoskeleton proteins
impaired axoplasmic transport
oxidative stress
Origin of ALS
Origin of ALS
(Bruijn LI et al. 2004 Annu Rev Neurosci)(Al-Chalabi, A. and P.N. Leigh 2000 Curr Opin Neurol)
(Conwit, R.A. 2006 J Neurol Sci)
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glutamate excitotoxicity
NMDA receptor
D-serineD-serine
Motor neuron death (apoptosis)
overdosage
(John M et al. PNAS 2010)
glutamate
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G72G72
D-serine D-serineD-serine
pyruvatepyruvate
D-amino acid oxidase (DAO)D-amino acid oxidase (DAO)
NMDA receptor
High D-serine
excitotoxicity motor neuron death amyotrophic amyotrophic lateral sclerosis lateral sclerosis
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oxidative stress
ALS
sporadic ALS90~95%
familial ALS5~10%
mutations in the gene encoding Cu/Zn superoixde
dismutase 1 (SOD1)20%
(Rosen DR et al. Nature 1993)13
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NMDA receptor activity
14(Sacchi et al. JBC 2008)