漸凍症 amyotrophic lateral sclerosis. lou gehrig's disease 1939 jean-martin charcot...
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漸凍症amyotrophic lateral sclerosis
Lou Gehrig's disease
19319399
Jean-Martin Charcot
Amyotrophic lateral sclerosis (ALS)Amyotrophic lateral sclerosis (ALS)
(Rosen DR et al. Nature 1993)
18691869
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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.
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.
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.
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
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.
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
NMDA receptor activity
14(Sacchi et al. JBC 2008)