Fighting neurodegeneration with rapamycin: mechanistic insights

• Published in: Nature reviews. Neuroscience Vol. 12; no. 8; pp. 437 - 452
• Main Authors: Vila, Miquel, Bové, Jordi, Martínez-Vicente, Marta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2011; Nature Publishing Group
• Subjects: 631/92/609; 692/699/375/365; Anatomical correlates of behavior; Animal Genetics and Genomics; Behavioral psychophysiology; Behavioral Sciences; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell growth; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drug therapy; Fundamental and applied biological sciences. Psychology; Health aspects; Humans; Kinases; Medical sciences; Nerve Degeneration - drug therapy; Nerve Degeneration - metabolism; Nervous system; Neurobiology; Neurodegeneration; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Neurology; Neurosciences; Parkinson's disease; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rapamycin; review-article; Signal Transduction - drug effects; Signal Transduction - physiology; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases - metabolism; United States; Spain; Cell proliferation; Nervous system diseases; Growth; Alzheimer disease; Ageing; Huntington disease; Parkinson disease; Review; Genetic disease; Cerebral disorder; Vertebrata; Experimental disease; Mammalia; Protein synthesis; Spinocerebellar ataxia; Central nervous system disease; Degenerative disease; Models; Extrapyramidal syndrome
• ISSN: 1471-003X; 1471-0048; 1469-3178
• DOI: 10.1038/nrn3068

Key Points
Multiple independent studies have recently shown that rapamycin, a US Food and Drug Administration (FDA)-approved antibiotic and immunosuppressant currently used to prevent rejection in organ transplantation, can provide therapeutic benefit in experimental models of several age-linked neurodegenerative diseases, including Parkinson's disease, Huntington's disease, Alzheimer's disease and spinocerebellar ataxia type 3.
Rapamycin is able to extend lifespan in various species, including mice, even when starting the treatment late in life.
Rapamycin inhibits the activity of mammalian target of rapamycin (mTOR), an intracellular serine/threonine protein kinase that is central in various cellular processes, including cell growth and proliferation, protein synthesis and autophagy. mTOR also has a key role in brain development and contributes to several functions in the adult normal brain, including synaptic plasticity, learning and memory.
Because of the multiplicity of mTOR downstream signalling pathways, different molecular mechanisms have been proposed to underlie rapamycin's neuroprotective effects in experimental models of neurodegeneration, such as induction of autophagy, decreased mitochondria-dependent apoptosis, blockade of cap-dependent translation of pro-cell death proteins and promotion of cap-independent translation of pro-survival factors. These mechanisms are not mutually exclusive and may act in concert to mediate the beneficial actions of rapamycin in neurodegeneration.
The potential therapeutic use of rapamycin, or some of its analogues, as disease-modifying agents in neurodegenerative conditions is discussed and possible limitations are taken into account, such as unfavourable physicochemical properties, undesirable side effects or potential alterations associated with chronic usage.
Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), has neuroprotective effects in models of several neurodegenerative diseases. In this Review, Vila and colleagues discuss the mechanisms by which rapamycin exerts neuroprotection, including effects on autophagy and apoptosis, and on the translation of pro-death and pro-survival proteins.
A growing number of studies point to rapamycin as a pharmacological compound that is able to provide neuroprotection in several experimental models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3. In addition, rapamycin exerts strong anti-ageing effects in several species, including mammals. By inhibiting the activity of mammalian target of rapamycin (mTOR), rapamycin influences a variety of essential cellular processes, such as cell growth and proliferation, protein synthesis and autophagy. Here, we review the molecular mechanisms underlying the neuroprotective effects of rapamycin and discuss the therapeutic potential of this compound for neurodegenerative diseases.