Autophagy, lithium, and amyotrophic lateral sclerosis

Abstract

In this article we provide an overview of the intersection between amyotrophic lateral sclerosis (ALS) and the autophagy pathway and discuss the potential protective effects of lithium through mechanisms that recruit autophagy and other effects. The autophagy pathway is recruited during motor neuron (MN) death both in vitro and in vivo. Despite a few controversial issues concerning the significance (detrimental/protective) of autophagy in ALS, recent findings indicate a protective role. Lithium in low doses is a well-known autophagy inducer that clears misfolded proteins and altered mitochondria from MNs. Moreover, lithium preserves mitochondria and sustains their genesis. This effect is replicated by rapamycin, which is an autophagy inducer but with a different mechanism from lithium. Lithium also increases the number of Renshaw cells that are affected early during the progression of experimental ALS. Again, lithium has been reported to decrease glial proliferation in the ALS spinal cord and induces sprouting in corticospinal fibers. Muscle Nerve 40: 173-194, 2009.

Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate

“…The activation of autophagy may be neuroprotective in ALS (Fornai et al, 2008b;Pasquali et al, 2009). Lithium delayed disease progression in ALS patients.…”

Psychopharmacological Neuroprotection in Neurodegenerative Diseases, Part III: Criteria-Based Assessment: A Report of the ANPA Committee on Research

“…Drug dose can make a difference in effects. Low doses of lithium, for example, activate autophagy in extraneuronal models, 101 whereas these same doses may be ineffective in activating other neuroprotective functions. On the other hand, in preclinical models of neuroprotection, a bellshaped rather than open-ended sigmoid-shaped doseresponse curve is often encountered.…”

Autophagy and Neuronal Cell Death in Neurological Disorders

“…Autophagosomes are frequently seen in otherwise normal-appearing perikarya of motor neurons in sporadic ALS patients (Sasaki 2011) and significantly are elevated by the time clinical symptoms appear (Venkatachalam et al 2008;Pasquali et al 2009). Autophagosomes and autolysosomes appear in close association with p62-positive inclusions and both become more frequent in degenerating neurons (Sasaki 2011).…”