Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium
Open accessAbstract
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.
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Despite early enthusiasm over lithium in patients and mouse models, five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients.
“Despite early enthusiasm over lithium in patients and mouse models [505,506], five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients [507–511].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [506]
Lithium-induced mitophagy and mitochondrial biogenesis improve mitochondrial morphology in motor neurons of G93A SOD-1 ALS mice.
“lithium-induced induction of mitophagy (38, 101) and mitochondrial biogenesis (101) improves mitochondrial morphology in motor neurons of a G93A SOD-1 mouse model of ALS.”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [38]
Defective mitophagy underlies progression of motor neuron death in ALS.
“Defective mitophagy underlies the progression of motor neuron death in Amyotrophic lateral sclerosis (ALS) (38).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [38]
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- Authors
- Fornai, F., Longone, P., Ferrucci, M., Lenzi, P., Isidoro, C., Ruggieri, S., & Paparelli, A.
- Affiliations
- University of Pisa (IT)
- Fondazione Santa Lucia (IT)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Istituto Neurologico Mediterraneo (IT)
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2008-05-16
- Volume
- 4
- Issue
- 4
- Pages
- 527-530
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- OpenAlex
- W2034703986
- Cited by
- 111
- References
- 24
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 4 · 2016: 4 · 2015: 9 · 2014: 7 · 2013: 4 · 2012: 8
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Autophagy (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, lithium, mitochondrial biogenesis, neuroprotection, calbindin-D28k, glial cell proliferation, neuronal differentiation, protein aggregates, neurodegeneration, spinal cord
- MeSH terms
- Amyotrophic Lateral Sclerosis, Astrocytes, Autophagy, Clinical Trials as Topic, Humans, Mitochondria, Neurons, Spinal Cord, Stem Cells, Antipsychotic Agents, Signal Transduction, Lithium Compounds, Neuroprotective Agents
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