Fighting neurodegeneration with rapamycin: mechanistic insights

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.

Abstract

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.

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Figure 1: Composition and rapamycin-mediated regulation of mammalian target of rapamycin complexes.
Figure 2: Target of rapamycin signalling pathways.
Figure 3: Potential sites of rapamycin's therapeutic actions in experimental Parkinson's disease.

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Acknowledgements

This work was supported by the European Commission Marie Curie Excellence Grant (to M.V.), Marie Curie International Reintegration Grant (to M.V.), Fundació la Caixa, Spain (to M.V.), Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII), Spain (to M.V. and M.M-V.) Ministerio de Ciencia e Innovació (MICINN), Spain (to M.V. and M.M-V.) and Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Spain (to M.V.).

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Supplementary information

Supplementary information S1 (table)

Effects of rapamycin in Parkinson's disease-related experimental in vitro models (PDF 351 kb)

Supplementary information S2 (table)

Effects of rapamycin in Huntington's disease-related experimental in vitro models (PDF 328 kb)

Supplementary information S3 (table)

Effects of rapamycin in other experimental in vitro models of neurodegeneration (PDF 321 kb)

Supplementary information S4 (table)

Effects of rapamycin on aging (PDF 286 kb)

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Glossary

Cap-dependent translation

A form or mRNA translation in which a nuclear modification at the 5′ end of eukaryotic mRNAs, called the cap structure, acts as a tag for the recruitment of the 40S ribosomal subunit and the eukaryotic translation initiation factor 4F (eIF4F) complex to initiate translation.

AGC kinases

A subfamily of serine/threonine protein kinases that, based on sequence alignments of their catalytic kinase domain, are related to cyclic AMP-dependent protein kinase 1 (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC). AGC kinases control critical cellular processes, such as cell growth, differentiation and cell survival, and their mutation and/or dysregulation contributes to the pathogenesis of many human diseases, including cancer and diabetes.

MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). MPTP is a by-product of the chemical synthesis of a meperidine analogue with potent heroin-like effects that causes in humans a syndrome mimicking the core neurological symptoms and relatively selective dopaminergic neurodegeneration of Parkinson's disease. In primates and mice, MPTP kills dopaminergic neurons and has been extensively used to model dopaminergic neurodegeneration linked to Parkinson's disease.

6-OHDA

6-OHDA is a noradrenergic analogue that triggers dopaminergic neurodegeneration when administered directly into the nigrostriatal system of rodents.

MPP+

(1-methyl-4-phenylpyridinium). The active metabolite of MPTP. MPTP is a pro-toxin that after crossing the blood–brain barrier is metabolized into 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) by the enzyme monoamine oxidase B (MAO-B) in non-dopaminergic cells and then, probably by spontaneous oxidation, to MPP+. MPP+ enters dopaminergic neurons through dopamine transporters, for which it has high affinity, and is concentrated by an active process within the mitochondria, where it impairs mitochondrial respiration by inhibiting complex I of the electron transport chain.

Rotenone

An inhibitor of mitochondrial complex I that is widely used as an insecticide and piscicide. In rodents, intravenous and subcutaneous infusion of rotenone produces nigrostriatal dopaminergic neurodegeneration, loss of intrinsic striatal neurons and formation of proteinaceous inclusions.

Paraquat

A herbicide that induces dopaminergic cell loss and α-synuclein accumulations in rodents when administered systemically.

3-NP

(3-nitro-propionic acid). An inhibitor of mitochondrial complex II of the electron transport chain that is used to mimic striatal lesions linked to Huntington's disease.

Light-gathering rhabdomeres

The compound eye of Drosophila spp. comprises many units, called ommatidia, each containing eight photoreceptor neurons with light-gathering parts called rhabdomeres.

R6/2 model of Huntington's disease

(HDQ150 mice). Transgenic mice (strain of origin CBA × C57BL/6) for the 5′ end of the human Huntington's disease gene carrying approximately 160 ± 10 glutamines. Mice exhibit a progressive neurological phenotype that mimics many features of Huntington's disease.

Beclin 1

Mammalian beclin 1 (known as autophagy-related protein 6 (Atg6) or vacuolar protein sorting-associated protein 30 (Vps30) in yeast) is a protein involved in autophagic vesicle nucleation. It associates with several other proteins, such as Vps34 or Vps15 in yeast and activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) or UV radiation resistance-associated gene protein (UVRAG) in mammals, to form a protein complex that initiates the formation of the autophagosome.

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Bové, J., Martínez-Vicente, M. & Vila, M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 12, 437–452 (2011). https://doi.org/10.1038/nrn3068

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