VIEWS AND COMMENTARIES Autophagy 8:1, 147–151; January 2012; G 2012 Landes Bioscience

Rapamycin activates autophagy in Hutchinson-Gilford syndrome Implications for normal aging and age-dependent neurodegenerative disorders

John J. Graziotto,1 Kan Cao,2 Francis S. Collins3 and Dimitri Krainc1,* 1Department of Neurology; Massachusetts General Hospital; MassGeneral Institute for Neurodegenerative Disease; Harvard Medical School; Charlestown, MA USA; 2Department of Biology and Molecular Genetics; University of Maryland; College Park, MD USA; 3Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA

hile rapamycin has been in use for to display alopecia, growth retardation, Wyears in transplant patients as an bone abnormalities, osteoporosis and scler- antirejection drug, more recently it has odermatous skin by one year of age.1,3 The shown promise in treating diseases of cardiovascular system is severely affected aging, such as neurodegenerative disor- and, sadly, HGPS patients most often © 2012 Landesders and atherosclerosis. We Bioscience. recently succumb to myocardial infarction or reported that rapamycin reverses the stroke in their early teens.1 The most cellular phenotype of fibroblasts from common form of HGPS is caused by a de children with the premature aging disease novo mutation in exon 11 of the lamin Hutchinson-Gilford progeria syndrome A gene. This mutation activates a splice (HGPS). We found that the causative donor, leading to production of a lamin Do notaberrant , distribute. progerin, was cleared A variant with an internal deletion of through autophagic mechanisms when 50 amino acids. This protein is termed the cells were treated with rapamycin, progerin4 and is defective in a critical post- suggesting a new potential treatment for translational processing step. The normal HGPS. Recent evidence shows that processing of the lamin A protein involves progerin is also present in aged tissues farnesylation of the C terminus by farne- of healthy individuals, suggesting that syltransferase, followed by cleavage by progerin may contribute to physiological the metalloproteinase Zmpste24, which aging. While it is intriguing to speculate removes 18 amino acids at the C terminus that rapamycin may affect normal aging and yields mature lamin A.5,6 The farne- in humans, as it does in lower organisms, sylation of lamin A is an essential step in it will be important to identify safer this process, as it targets the protein to the analogs of rapamycin for chronic treat- inner nuclear membrane surface where ments in humans in order to minimize it is finally cleaved by Zmpste24 to yield toxicity. In addition to its role in HGPS mature lamin A.7 In HGPS, the mutant and normal aging, we discuss the poten- progerin protein has lost this cleavage site, tial of rapamycin for the treatment of age- resulting in permanent farnesylation. The dependent neurodegenerative diseases. retention of the farnesylated C terminus is thought to cause the progerin protein Keywords: progerin, rapamycin, to remain anchored in the nuclear mem- autophagy, aging, neurodegeneration, HGPS brane, with other of the normally progeria fluid nuclear scaffold attached to it. Submitted: 09/22/11 Hutchinson-Gilford progeria syndrome During mitosis, when the scaffold has to (HGPS) results from a de novo mutation disassemble and reassemble, the mutant Accepted: 10/06/11 in the gene for the protein, protein is highly disruptive. With increas- http://dx.doi.org/10.4161/auto.8.1.18331 lamin A, and is observed in about 1 in ing numbers of cell divisions, several 1,2 *Correspondence to: Dimitri Krainc; 4 million live births. Patients with phenotypes can be observed including Email: [email protected] HGPS appear normal at birth, but begin nuclear blebbing, which is seen in primary

www.landesbioscience.com Autophagy 147 fibroblasts from HGPS patients, along neurodegenerative diseases. These effects ALFY normally resides in the cell nucleus, with a reduced growth rate and increased are presumed to be due to the inhibition it will be of particular interest to further senescence in culture.8,9 Of note, muta- of mTOR by rapamycin, and are at least examine its role in clearance of nuclear tions in humans and mice that disrupt in part dependent on autophagy.17,20,21 progerin. Zmpste24, resulting in permanent farne- We recently found that the mTOR Interestingly, in the context of HGPS, sylation of an otherwise normal lamin inhibitor rapamycin rescues the cellular rapamycin also has been reported to have A, also give rise to phenotypes similar to phenotype of HGPS fibroblasts and a beneficial effect on mouse models prone HGPS, supporting the hypothesis that decreases the amount of progerin pro- to cardiovascular disease phenotypes. In retention of the farnesylated C terminus tein through autophagic clearance.22 three separate studies involving apoE leads to the cellular phenotype.6,10,11 Co-treatment with rapamycin and the knockout mice or LDLR knockout mice, autophagy inhibitors bafilomycin A1 or rapamycin reduces arteriosclerotic lesions Therapeutic Strategies for HGPS 3-methyladenine slow the enhanced clear- despite the severe hypercholesterolemia ance, suggesting that progerin is being in these mice, even when fed a high-fat Without treatment, HGPS is a uniformly cleared through autophagy. Further experi- diet.29-31 Because the cardiovascular disease fatal disorder. A promising new therapy, ments using genetic inhibition of auto- component of HGPS leads to devastating now being subjected to a clinical trial, is phagy by ATG7 knockdown confirmed this heart attacks or strokes, it will be of the use of farnesyltransferase inhibitors result. interest to examine if rapamycin confers (FTIs). FTIs are experimental drugs To examine the mechanism of progerin any benefit on the cardiovascular aspects originally developed for cancer therapy, clearance in further detail, we next exa- of HGPS by promoting clearance of because of their predicted effect on the mined the ubiquitination status of pro- progerin in cardiovascular tissues. The oncoprotein Ras, which also requires gerin. Protein ubiquitination has recently G608G mouse model of HGPS has a farnesylation for its function.12 While emerged as an important signal for selec- cardiovascular phenotype that shows ©FTIs have 2012 been somewhat disappointing Landestive autophagic clearance that Bioscience. involves improvement with FTI treatment.9 in their effectiveness against cancer, FTI autophagy adaptor proteins that bind both Experiments are now underway with this treatment reduces nuclear blebbing in ubiquitinated cargo and autophagosomes mouse model of HGPS to see whether HGPS fibroblasts and cell lines trans- (e.g., p62). Specifically, different effects everolimus (an analog of rapamycin) is fected with progerin.13,14 Furthermore have been described for different types capable of preventing the cardiovascular FTIs improve phenotype and life span in of polyubiquitin chains; for example, the disease phenotype. mouse models of progeria.Do9,15 It is thought notK48 polyubiquitin distribute. (polyUb) chain is that FTIs, by preventing farnesylation recognized by, and promotes degradation Rapamycin and Autophagy of progerin, reduce the accumulation of of proteins through, the proteasome, in Neurodegenerative Diseases progerin at the nuclear rim, reducing the whereas the K63 polyUb chain promotes damaging effects of the mutant protein on autophagic clearance of oligomeric and It is thought that the accumulation of the the nucleus.13 The outcome of an open- aggregated proteins.23-25 We found that progerin protein in HGPS underlies the label HGPS clinical trial of the FTI progerin is preferentially ubiquitinated progression of the disease phenotype. This lonafarnib is awaited with great interest. by K63-linked polyUb chains, suggesting is true for other proteinopathies that are that it is a substrate for autophagy. Addi- caused by accumulation of mutated or Rapamycin Promotes Clearance tionally, progerin co-immunoprecipitates improperly processed protein. Among of Progerin with the autophagic adaptor protein p62, them are several neurodegenerative dis- further demonstrating that the clearance eases, including Huntington, Parkinson Rapamycin is an FDA-approved drug that of progerin is mediated by autophagy. and Alzheimer diseases. Recent evidence has been used historically to suppress the Finally, via immunofluorescence micro- suggests that boosting autophagy in mod- rejection of transplanted organs, usually scopy, we found that progerin colocalizes els of these disorders can reduce the in combination with other immunosup- with both p62 and the autophagy linked accumulation of the disease protein and pressants. In addition to its historical use FYVE protein, ALFY, in the presence of protect against toxicity associated with as an immunosuppressant, there is mount- rapamycin. Interestingly, upon treatment protein aggregation. ing pre-clinical evidence that rapamycin with rapamycin, less progerin is seen in the For example, Huntington disease is or analogs of rapamycin extend life span nuclei, and it instead colocalizes with p62 caused by an abnormal expansion of the in a number of species including flies and ALFY in the juxtanuclear cytoplasm, polyglutamine tract in the huntingtin and mice.16-18 The life-span extending suggesting that ALFY and p62 are instru- protein. This mutant form of huntingtin effect in mice is observed even if treatment mental in the clearance of progerin. accumulates inside neurons, forms aggre- is not started until the mice are already Importantly, because p62 and ALFY can gates and eventually causes cell death. aged.19 Furthermore, there is evidence also interact with the mammalian homolog Cell culture models overexpressing mutant that rapamycin and rapamycin derivatives of Atg8 (LC3), they therefore represent huntingtin are protected from toxicity and are useful in delaying or treating age- a functional link between ubiquitinated clear huntingtin faster when treated with related conditions, including cancers and cargo and autophagosomes.26-28 Since the autophagy-enhancing drug rapamycin,

148 Autophagy Volume 8 Issue 1 leading to less aggregation.32 This finding amyloid-β, which therefore inhibits auto- that divide rapidly, including has been extended in vivo, in both flies phagy. Rapamycin restores autophagy and populations responsible for tissue home- and mice. Fruit flies expressing mutant reduces amyloid-β despite this baseline ostasis. Indeed, Scaffidi et al.49 showed huntingtin in photoreceptor neurons are inhibition of autophagy. that progerin expression interferes with protected from rhabdomere degeneration Together, these studies demonstrate the differentiation potential of human when fed rapamycin.33,34 Mouse models that in neurodegenerative diseases where mesenchymal stem cells (hMSC), which expressing mutant huntingtin in the brain misfolded proteins accumulate, boosting in turn gives rise to many of the affected also demonstrate less aggregation in the autophagy with pharmacological agents tissues in HGPS. This raises the possibi- striatum when treated with the rapamy- can prove beneficial. As in HGPS, rapa- lity that sporadic expression of aberrant cin analog temsirolimus.33 Huntingtin mycin shows promise in various models progerin in physiological aging could is a substrate for autophagic clearance,27 of neurodegenerative disorders; however, affect tissue homeostasis by inhibiting the and the protective effects of rapamycin it will be important to identify safer ability of stem cells to regenerate damaged in these models occur at least in part analogs of rapamycin for chronic treat- cells. through the activation of autophagy,35-37 ments in patients. Most recently, activation of progerin and the subsequent clearance through expression in normal cells has been linked degradation of unnecessary or toxic com- Progerin and Normal Aging to telomere dysfunction. Non-HGPS ponents inside the cell.38,39 cells expressing progerin have shorter A characteristic feature of Parkinson In HGPS, progerin is produced as a result telomeres than non-progerin-expressing disease (PD) is the presence of intracellular of a mutation that activates a cryptic cells, and inducing telomere damage inclusions known as Lewy bodies. These splice site in the lamin A gene. However, experimentally also upregulates progerin inclusions contain a-synuclein, which in normal cells, this unmutated cryptic expression through increased usage of the accumulates in PD. Accumulation of toxic splice site is also used sporadically, lead- cryptic splice site in LMNA (and many ©a-synuclein 2012 species further affects theLandesing to production of progerin Bioscience. protein other changes in alternative splicing).50 lysosomes’ ability to clear a-synuclein.40 in non-HGPS individuals.46,47 Increased Interestingly, there is also evidence that Increasing autophagy increases clearance activation of this cryptic splice site progerin expression actually induces telo- of a-synuclein in cell models that over- appears to correlate with incipient cell mere damage,51 raising the possibility of express the mutant proteins,41 and mouse senescence, and the progerin protein the existence of a positive feedback loop models which overexpress and accumulate appears to accumulate with increasing between telomere damage and progerin a-synuclein also showDo less accumulation notage in skin biopsies,distribute.47 as well as in culture. expression that is capable of driving when treated with rapamycin because of Interestingly, an early report showed that programmed senescence. increased autophagy and lysosomal activa- oligonucleotide based inhibition of the As a whole, these findings raise the tion.42 Furthermore, in mouse models of cryptic splice site in LMNA reduces the likelihood that splicing of LMNA, leading PD treated with the toxin MPTP, auto- changes in nuclear architecture found in to increasing progerin production after phagosomes accumulate due to a decrease cells from aged individuals, and reduces multiple cell divisions, affects physiologi- in lysosomal function. Accumulation of markers of senescence as well,46 raising cal aging in normal individuals and con- autophagosomes and loss of lysosomes is the hypothesis that these low levels of tributes functionally to programmed cell also found in postmortem PD brain, and sporadic progerin production could con- senescence. Although progerin accumula- Lewy bodies are positive for autophagoso- tribute to the aging process. tion is just one part of the many phy- mal markers. In the MPTP mouse model, Another recent study by Olive et al.48 siological changes that occur in the aging rapamycin treatment is able to restore looked for the presence of progerin in process, treatments that enhance clearance lysosomal levels, decrease autophagosome non-HGPS arteries in 29 individuals of progerin or prevent its production accumulation, and protect against dopa- ranging in age from 1 mo to 97 y. They could have aging-related health benefits minergic cell death.43 found a statistically significant increase over the long-term. Alzheimer disease is characterized in the amount of progerin-positive cells It will therefore be of interest to exa- pathologically by the presence of amyloid with age, ranging from an average of mine whether upregulation of autophagy plaques, consisting of amyloid-β and 1 in 1,000 cells at 1 mo, to ~20 in 1,000 by rapamycin could enhance clearance of neurofibrillary tangles, which are intra- cells at 97 y in the adventitia. This progerin, as well as other proteins that cellular inclusions composed of hyper- represents an increase of 3.34% per accumulate during normal aging. phosphorylated tau. In several mouse year.48 In cells where progerin was pre- and fly models of Alzheimer disease, sent, it was found as progerin-positive Therapeutic Limitations upregulation of autophagy improves cytoplasmic puncta, suggesting that it of Rapamycin some of the behavioral and pathological accumulates in certain cells over time after phenotypes, and reduces amyloid β and repeated mitoses. Rapamycin treatment is associated with tau related toxicities.38,44,45 Interestingly Progerin accumulation in normal cells side effects, some of which require dis- in Alzheimer models, mTOR is acti- would presumably have negative conse- continuation of treatment (in up to 39% vated, potentially by the presence of quences, particularly in cell populations of patients), at least at the doses used in

www.landesbioscience.com Autophagy 149 transplant patients. Side effects include Another potential drawback for the use might help increase progerin clearance gastrointestinal symptoms, edema, infec- of rapamycin in children with HGPS is even more than rapamycin alone.41,56 tion, delayed wound healing, high choles- the potential effect on growth and deve- Finally, co-administration of rapamycin terol and triglyceride levels, anemia, and lopment. This could pose a problem for with the FTIs currently in clinical trials interstitial pneumonitis.52,53 The intersti- drugs that inhibit mTOR, which is a for HGPS could also have an additive tial pneumonitis is a particularly severe master regulator of cellular growth and effect on progerin clearance. While rapa- side effect and can be life threatening. proliferation. A recent study involving mycin clears farnesylated progerin through Some of these effects may be due to pediatric kidney transplant recipients autophagy, FTIs presumably help by limit- off-target effects of rapamycin. The use undergoing treatment with rapamycin ing the amount of farnesylated progerin of alternative, more specific inhibitors suggests that growth rate is reduced in produced in the first place. Perhaps a of the mTORC1 pathway, such as the treated group, at least for the 2 y of combination treatment involving both everolimus (RAD001) may be safer. data available.55 Nevertheless, considering FTIs and rapamycin would be even more Everolimus also has better solubility in the severity of the disease, the benefits efficacious in clearing progerin and even- aqueous solution and is more stable may outweigh the potential side effects, tually treating HGPS. compared with rapamycin. Several case and perhaps they can be controlled with reports indicate resolution of pneumoni- careful dosing schedules, for instance, Conclusion tis upon switching from sirolimus to intermittent periods of treatment, followed everolimus.54 by recovery periods, rather than chronic The last several years of studies on HGPS In cases where the potential benefits treatment. have yielded important insights about the outweigh the potential for side effects, Alternatively, mTOR-independent sti- role of progerin in this disease and in the such as in devastating diseases like HGPS, mulators of autophagy such as trehalose normal aging process. Our recent finding neurodegenerative disease and cancer, or lithium could be explored to sidestep that rapamycin clears the progerin protein ©rapamycin and2012 rapamycin derivatives mayLandesthe potential developmental issues.Bioscience. It is through autophagy and reverses the cel- offer a new treatment strategy. However, not known, however, if these approaches lular phenotypes of HGPS fibroblasts the use of rapamycin in otherwise healthy will be effective in clearing the progerin provides a new target for treatment of people to slow the aging process would protein. In neurodegenerative disease HGPS: the clearance of progerin. Given require safer alternatives and/or lower models, these mTOR-independent com- the recent findings that progerin is also doses than those typically given to trans- pounds have an additive effect on auto- expressed during physiological aging, this plant patients to mitigateDo the chance not of phagy induction distribute. when co-administered finding possibly has implications for the side effects. with rapamycin, so it is possible that they normal aging process as well.

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