ALS is a degenerative neurological disease of motor neurons which leads to eventual end paralysis and death from respiratory failure Free radicals, excess glutamate, and excess calcium release contribute to the motor neuron cell death. There is the ‘die forward’ model of corticomotor neuron cell death where corticomotor neurons die first followed by denervation atrophy of the spinal motor neurons. The cortical innervations theory suggests that loss of muscular coordination and control occurs earlier than progressive weakness and denervation atrophy. The retrograde neuronal cell death theory applies to several more situations where backwards atrophy is the rule rather than the exception to the case.

Free radicals generated from singlet oxygen and free radical water species can cause cellular membrane

and mitochondrial cell damage, causing cell death spontaneously. Apoptosis is genetically programmed

cell death caused presumably by a redox balance fallout. Mutants such as the superoxide dismutase

one mutation in mice (SOD1) exhibit motor neuron disease. The mutants, interestingly, demonstrate

another genetic abnormality in abnormal prion gene expression. Prions are infective protein particles

which are responsible for prion spongiform encephalopathies, such as Creutzfeldt Jakob Disease or CJD.

The prions are approximately 120 amino acids in length and are the only protein thought to be

infectious in the central nervous system or otherwise. The prions do not have any nucleic acid but are

associated with wild type genes within the human, yeast, and and mammalian genomes.

The epidemiologists have shown that organophosphate pesticides predispose to ALS in human studies

involving Veterans and non-veterans. The epidemiology of ALS is characterized by redox gene

imbalances and and oxidant stresses both leading to abnormal prolonged oxidant stress. Lead and other

heavy metals can be chronic exposures leading to free radical damages which lead to other gene

abnormalities. These gene changes in turn cause further abnormal prion gene expression or oxidant

stress mitochondrial and or cellular membrane damage.

Electrophysiology has shown that abnormal cortical excitability occurs in sporadic but not homozygous

SOD1 mutants. Most of these studies have used transcranial magnetic stimulation to excite or

depolarize the cerebral motor cortex. The Nardone et al group showed that as ALS progresses the

cortical responses become more abnormal and diminish in responsivity. The hyperexcitability seen in

animal models is also observed in humans, where disease progression indicates worsening function.

There does not appear to be epileptic seizures associated with this hyperexcitability.

References: (to follow)

Limviphuvadh V, Tanaka S, Goto S, Ueda K, & M Kanehisa (2007) “Systems Biology, the Commanlity of

Protein Interaction Networks Determined in Neurodegenerative Disorders (NDDs)” Bioinformatics 23,

2129-2138.

Nardone R, Buffone E, Florio I, & F Tezzon (2005) Changes in Motor Cortex Excitability during Muscle

Fatigue in Amyotrophic Lateral Sclerosis” J Neurology, Neurosurgery, & Psychiatry 76: 429-431.

Schmidt S. et al. (2008) “Genes and Environmental Exposures in Veterans with Amyotrophic Lateral

Sclerosis : The GENEVA Study” Methods in Neuroepidemiology 30: 191-204.

Turner MR, et al. (2005) “Abnormal Cortical Excitability in Sporadic but not Homozygous D90A SOD1

ALS” J Neurology, Neurosurgery, & Psychiatry 76, 1279-1285.

Vucic S, & MC Kiernan (2006) “Novel Threshold Tracking Techniques Suggest that Cortical

Hyperexcitability in an Early Feature of Motor Neuron Disease” Brain 129, 2436-2446.