Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium

In a pilot clinical study that we recently published we found that lithium administration slows the progression of Amyotrophic Lateral Sclerosis (ALS) in human patients. This clinical study was published in addition with basic (in vitro) and pre-clinical (in vivo) data demonstrating a defect of autophagy as a final common pathway in the genesis of ALS. In fact, lithium was used as an autophagy inducer. In detailing the protective effects of lithium we found for the first time that this drug stimulates the biogenesis of mitochondria in the central nervous system and, uniquely in the spinal cord, it induces neuronogenesis and neuronal differentiation. In particular, the effects induced by lithium can be summarized as follows: (i) the removal of altered mitochondria and protein aggregates; (ii) the biogenesis of well-structured mitochondria; (iii) the suppression of glial proliferation; (iv) the differentiation of newly formed neurons in the spinal cord towards a specific phenotype.In this addendum we focus on defective autophagy as a “leit motif” in ALS and the old and novel features of lithium which bridge autophagy activation to concomitant effects that may be useful for the treatment of a variety of neurodegenerative disorders. In particular, the biogenesis of mitochondria and the increase of calbindin D 28K-positive neurons, which are likely to support powerful neuroprotection towards autophagy failure, mitochondriopathy, and neuronal loss in the spinal cord.Addendum to: Fornai F, Longone P, Cafaro L, Kastsiuchenka O, Ferrucci M, Manca ML, Lazzeri G, Spalloni A, Bellio N, Lenzi P, Modugno N, Siciliano G, Isidoro C, Murri L, Ruggieri S, Paparelli A. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2008; 105:2052-2057.