漸凍症 amyotrophic lateral sclerosis

Lou Gehrig's disease 1939 Jean-Martin Charcot Amyotrophic lateral sclerosis (ALS) (Rosen DR et al. Nature 1993)

ALS: Epidemiology ALS is the most common form of motor neuron disease. Sporadic forms (unknown cause) account for about 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 (Bruijn LI et al Annu Rev Neurosci) (Al-Chalabi, A. and P.N. Leigh 2000 Curr Opin Neurol) (Conwit, R.A J Neurol Sci) 10

 glutamate excitotoxicity NMDA receptor D-serine Motor neuron death (apoptosis) overdosage (John M et al. PNAS 2010) glutamate 11

G72 D-serine D-serine pyruvate D-amino acid oxidase (DAO) NMDA receptor High D-serine excitotoxicitymotor neuron death amyotrophic lateral sclerosis 12

 oxidative stress ALS sporadic ALS 90~95% familial ALS 5~10% 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)