Pathophysiology of ALS. Commonly known as Lou Gehrig’s disease, ALS is the most frequent motor neuron disease of adults, afflicting about 30,000 individuals in the United States (1 in 2,000 lifetime risk). The genetic basis of ALS pathophysiology is largely unknown; about 10% of cases have a familial basis, and about 20% of these are known to be due to dominant mutations in the gene coding for Cu/Zn superoxide dismutase (SOD1).¹ The large majority of cases (90%), however, are sporadic, and no genetic mutations have so far been identified with certainty. The clinical features of the disease are the same in both types.

As in many other neurodegenerative diseases, abnormal protein aggregates are found in all forms of ALS (and in SOD1-mediated mouse models of ALS).² Dysfunction of the ubiquitin-proteasome system for misfolded protein disposal may be involved, because the aggregates react strongly with ubiquitin antibodies in both SOD1-mediated familial ALS and SOD1-mediated mouse models.³ However, in the last analysis, it is still unknown whether the aggregates are a fundamental aspect of the disease process or are the result of a protective mechanism that sequesters toxic products.²

In vitro studies of motor neurons from the SOD1 G93A mouse model of ALS have identified defects in both macroautophagy and mitochondrial function.⁴ (Macroautophagy is a cellular mechanism functioning in the phagosome lysosome pathway for clearance of bulk aggregative cytoplasmic proteins. In ALS mouse models, accumulations of ubiquitin, and SOD1 have been identified.⁴)

Whatever the genetic and pathophysiologic basis of ALS may be, the result is progressive motor neuron death (both upper and lower motor neurons in the corticobulbar, corticospinal, and spinal tracts), which inevitably leads to death of individuals 3–5 years after diagnosis (about 1 year in the bulbar form). Although riluzole is the only FDA approved drug for ALS, to date, no truly effective treatment has been found.

Experimental Lithium Effects. In the SOD1 G93A mouse model of ALS, lithium administration results in significant neuroprotection, resulting in delay of disease onset and increased lifespan. In these motor neurons in vitro, lithium has been shown⁴ to (1) reactivate the macroautophagy function (through a mechanism of inositol monophosphatase inhibition⁵), (2) remove defective mitochondria and induce mitogenesis [Figure 1]), (3) suppress glial cell activation (astrocytosis), which has been implicated in the ALS disease process, (4) decrease ubiquitin, and SOD1 aggregation, (5) suppress glutamatergic excitotoxicity, and (6) possibly induce neurogenesis (in the spinal cord). These experimental results prompted a pilot study by Fornai et al on the clinical effects of lithium in ALS patients.⁶