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)