REST is lost in mild cognitive impairment and Alzheimer’s disease

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown.


A study shows that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons.

REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes.

Oxidative stress

Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration.

A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling.

However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins.

Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity.

Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

RE1-Silencing Transcription factor (REST)

RE1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a protein which in humans is encoded by the REST gene, and acts as a transcriptional repressor.[3][4][5]REST is expressly involved in the repression of neural genes in non-neuronal cells.[5][6] Many genetic disorders have been tied to alterations in the REST expression pattern, including colon and small-cell lung carcinomas found with truncated versions of REST.[7] In addition to these cancers, defects in REST have also been attributed a role in Huntington Disease, neuroblastomas, and the effects of epileptic seizures and ischemia.

This gene encodes a transcriptional repressor which represses neuronal genes in non-neuronal tissues. It is a member of the Kruppel-type zinc finger transcription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element (NRSE, also known as RE1). The protein is also found in undifferentiated neuronal progenitor cells, and it is thought that this repressor may act as a master negative regulator of neurogenesis. Alternatively spliced transcript variants have been described; however, their full length nature has not been determined.[3] REST is found to be down-regulated in elderly people with Alzheimer’s disease.[8]

REST contains 8 Cys2His2 zinc fingers and mediates gene repression by recruiting several chromatin-modifying enzymes.

Interesting to note that REST strongly correlate with increased longevity. REST levels are highest in the brains of people who lived up to be 90 – 100s and remained cognitively intact. Levels stayed high specifically in the brain regions vulnerable to Alzheimer’s, suggesting that they might be protected from dementia. It is assumed that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity.[8] REST is also responsible for ischaemia induced neuronal cell death, in mouse models of brain ischaemia. Ischaemia, which results from reduced blood profusion of tisssues, decreasing nutrient and oxygen supply, induces REST transcription and nuclear accumulation, leading to the epigenetic repression of neuronal genes leading to cell death.[10] The mechanism beyond REST induction in ischaemia, might be tightly linked to its oxygen-dependent nuclear translocation and repression of target genes in hypoxia (low oxygen) where REST fulfils the functions of a master regulator of gene repression in hypoxia.

REST interacts with RCOR1

This gene encodes a protein that is well-conserved, downregulated at birth, and with a specific role in determining neural cell differentiation. The encoded protein binds to the C-terminal domain of REST(repressor element-1 silencing transcription factor).

RCOR1 interacts with HDAC1

Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2 MTA2, it deacetylates p53 and modulates its effect on cell growth and apoptosis.

HDAC1 interacts with HMG20B

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1-related is a protein that in humans is encoded by the HMG20B gene

Mapping Genes That Increase Lifespan

Comprehensive study finds 238 genes that affect aging in yeast cells.

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

Image shows yeast cells.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”


Other Buck Institute researchers involved in the study include: Mark A. McCormick (first co-author), Mitsuhiro Tsuchiya, Scott Tsuchiyama, Arianna Anies, Juniper K. Pennypacker, Shiena Enerio, Dan Lockshon, Brett Robinson, Ariana A. Rodriguez, Marc K. Ting, and Rachel B. Brem. A full list of authors is included in the paper.

Funding: This research was supported by NIH grants R01AG043080, R01AG025549, R01AG039390 and P30AG013280, as well as NIH training grants T32AG000266, T32AG000057 and T32ES007032 and the Ellison Medical Foundation.

The authors declare no competing financial interests.

Source: Anne Holden – Buck Institute
Image Credit: The image is adapted from the Buck Institute press release
Original Research: Abstract for “A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging” by Brian Kennedy et al. in Cell Metabolism. Published online October 8 2015 doi:10.1016/j.cmet.2015.09.008


A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

•4,698 deletions tested yields the most comprehensive yeast data set on aging
•Longevity clusters center on known, conserved biological processes
•Enrichment of lifespan-extending C. elegans orthologs suggests conservation
•Genome-wide information uncovered aging pathways such as tRNA transport

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

“Neural mechanisms supporting maladaptive food choices in anorexia nervosa” by Karin Foerde, Joanna E Steinglass, Daphna Shohamy and B Timothy Walsh in Nature Neuroscience. Published online October 12 2015 doi:10.1038/nn.4136


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Parkinson’s disease and Mitochondria as the oxygen-consuming power plants of human cells

  • Mitochondrial maintenance is essential for cellular and organismal function.
  • Maintenance includes reactive oxygen species (ROS) regulation, DNA repair, fusion–fission, and mitophagy.
  • Loss of function of these pathways leads to disease.

Mitochondria are the oxygen-consuming power plants of cells. They provide a critical milieu for the synthesis of many essential molecules and allow for highly efficient energy production through oxidative phosphorylation. The use of oxygen is, however, a double-edged sword that on the one hand supplies ATP for cellular survival, and on the other leads to the formation of damaging reactive oxygen species (ROS). Different quality control pathways maintain mitochondria function including mitochondrial DNA (mtDNA) replication and repair, fusion–fission dynamics, free radical scavenging, and mitophagy. Further, failure of these pathways may lead to human disease. We review these pathways and propose a strategy towards a treatment for these often untreatable disorders.

Regarding mitophagy, two landmark papers showed that PINK1 and Parkin, two proteins mutated in familial Parkinson’s disease, are involved in the selective degradation of damaged mitochondria 16 and 100. Loss of these proteins may contribute to the accumulation of damaged mitochondria and death of dopaminergic neurons in the substantia nigra in the mesencephalon.

Further support of a mitochondrial etiology in Parkinson’s disease comes from the early observations that exposure to various mitochondrial toxins leads to Parkinson’s disease in humans and rodents [101]. Interestingly, Parkinsonism is relatively rare in primary mitochondrial diseases indicating that mitochondrial dysfunction does not automatically lead to dopaminergic neuronal death.

Conversely, Parkinson’s disease is not characterized by the severe neurodegeneration that commonly debuts in early adulthood in primary mitochondrial diseases. This may indicate that alternative mitophagy pathways may compensate for defects in PINK1 or Parkin [102] or that mitophagy plays a relatively minor role in overall mitochondrial maintenance. Recent findings of defective mitophagy in neurodegenerative accelerated aging disorders do, however, support a significant role of this pathway in overall mitochondrial maintenance [49].

Mitochondrial genetics

Mitochondria are a dynamic network of organelles constantly adapting their morphology and function to accommodate the needs of the cell. They are composed of an outer membrane, an intermembrane space, a highly folded inner membrane (the cristae), and a matrix space. Due to the prokaryotic origin of this organelle, the inner mitochondria membrane contains a specialized phospholipid, cardiolipin, that is also found in bacteria. More importantly, mitochondria contain their own DNA. The human mitochondrial genome, mtDNA, is a small circular ∼16.6 kilobase molecule that resides inside the matrix space associated with the inner membrane of the mitochondria [1]. mtDNA in humans encodes 13 polypeptides, 22 tRNAs, and two ribosomal genes that are essential for oxidative phosphorylation, the metabolic process by which cells convert energy stored in a range of different substrates to ATP, which is the energetic currency of the organism. All of the remaining mitochondrial proteins, including gene products necessary for mtDNA replication, transcription, and DNA repair, are derived from nuclear genes and are imported into the mitochondria, typically, but not exclusively, via a mitochondrial targeting sequence [2]. In addition to the role of mitochondria in ATP production, this organelle is also central in apoptosis, heme and steroid synthesis, Ca2+ regulation, adaptive thermogenesis, and other processes. Proper mitochondrial function is therefore critical for organismal health.

An understanding of mtDNA inheritance and maintenance patterns is essential for comprehending mitochondrial dysfunction in disease. mtDNA is packaged into protein–DNA structures called nucleoids containing one or more mtDNA genomes within a single nucleoid. Additionally, there are a few to several thousand copies of mtDNA per cell varying with cell type [3]. Cells can simultaneously carry a mixture of normal and mutated mitochondrial genomes, a condition known as heteroplasmy. Mutant mtDNA can be propagated along with normal mtDNA, when there is no selection pressure against the mutant genome, thereby contributing to the high sequence evolution of mtDNA [4]. When a cell divides and the nucleoids are segregated between the two daughter cells, the proportion of mutant to normal mtDNA can shift [5]. This has important ramifications for mitochondrial disease since the relative proportion of mutant mtDNA molecules must reach a certain threshold before a disease phenotype is observed.

Bona fide primary mitochondrial diseases represent a heterogeneous group of disorders most often involving multiple organ systems leading to progressive degeneration and in many cases early death. Since the combined prevalence is estimated to be around 1:5000, a mitochondrial etiology should be considered when encountering any patient, particularly children, with multisystem pathology in tissues such as the central nervous system, heart, skeletal muscles, liver, and in rarer cases kidney [6]. The pathogenic mutation can be located either within the mitochondrial or nuclear genome and, as in the case of mutations in Twinkle or DNA polymerase γ (POLG), can give rise to a great diversity of clinical syndromes (Figure 1).

Life is the interplay between structure and energy, yet the role of energy deficiency in human disease has been poorly explored by modern medicine. Since the mitochondria use oxidative phosphorylation (OXPHOS) to convert dietary calories into usable energy, generating reactive oxygen species (ROS) as a toxic by-product, I hypothesize that mitochondrial dysfunction plays a central role in a wide range of age-related disorders and various forms of cancer. Because mitochondrial DNA (mtDNA) is present in thousands of copies per cell and encodes essential genes for energy production, I propose that the delayed-onset and progressive course of the age-related diseases results from the accumulation of somatic mutations in the mtDNAs of post-mitotic tissues. The tissue-specific manifestations of these diseases may result from the varying energetic roles and needs of the different tissues. The variation in the individual and regional predisposition to degenerative diseases and cancer may result from the interaction of modern dietary caloric intake and ancient mitochondrial genetic polymorphisms. Therefore the mitochondria provide a direct link between our environment and our genes and the mtDNA variants that permitted our forbears to energetically adapt to their ancestral homes are influencing our health today.

Figure 1  Human mitochondrial DNA map showing representative pathogenic and adaptive base substitution mutations. D-loop = control region (CR). Letters around the outside perimeter indicate cognate amino acids of the tRNA genes. Other gene symbols are defined in the text. Arrows followed by continental names and associated letters on the inside of the circle indicate the position of defining polymorphisms of selected region-specific mtDNA lineages. Arrows associated with abbreviations followed by numbers around the outside of the circle indicate representative pathogenic mutations, the number being the nucleotide position of the mutation. Abbreviations: DEAF, deafness; MELAS, mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; LHON, Leber hereditary optic neuropathy; ADPD, Alzheimer and Parkinson disease; MERRF, myoclonic epilepsy and ragged red fiber disease; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosum; LDYS, LHON + dystonia; PC, prostate cancer.


As a toxic by-product of OXPHOS, the mitochondria generate most of the endogenous ROS. ROS production is increased when the electron carriers in the initial steps of the ETC harbor excess electrons, i.e., remain reduced, which can result from either inhibition of OXPHOS or from excessive calorie consumption. Electrons residing in the electron carriers; for example, the unpaired electron of ubisemiquinone bound to the CoQ binding sites of complexes I, II, and III; can be donated directly to O2 to generate superoxide anion (O•-2). Superoxide O•-2 is converted to H2O2 by mitochondrial matrix enzyme Mn superoxide dismutase (MnSOD, Sod2) or by the Cu/ZnSOD (Sod1), which is located in both the mitochondrial intermembrane space and the cytosol. Import of Cu/ZnSOD into the mitochondrial intermembrane space occurs via the apoprotein, which is metallated upon entrance into the intermembrane space by the CCS metallochaperone (166, 207). H2O2 is more stable than O•-2 and can diffuse out of the mitochondrion and into the cytosol and the nucleus. H2O2 can be converted to water by mitochondrial and cytosolic glutathione peroxidase (GPx1) or by peroxisomal catalase. However, H2O2, in the presence of reduced transition metals, can be converted to the highly reactive hydroxyl radical (•OH) (Figure 2). Iron-sulfur centers in mitochondrial enzymes are particularly sensitive to ROS inactivation. Hence, the mitochondria are the prime target for cellular oxidative damage (241, 242).

The mitochondria are also the major regulators of apoptosis, accomplished via the mitochondrial permeability transition pore (mtPTP). The mtPTP is thought to be composed of the inner membrane ANT, the outer membrane voltage-dependent anion channel (VDAC) or porin, Bax, Bcl2, and cyclophilin D. The outer membrane channel is thought to be VDAC, but the identity of the inner membrane channel is unclear since elimination of the ANTs does not block the channel (98). The ANT performs a key regulatory role for the mtPTP (98). When the mtPTP opens, ΔP collapses and ions equilibrate between the matrix and cytosol, causing the mitochondria to swell. Ultimately, this results in the release of the contents of the mitochondrial intermembrane space into the cytosol. The released proteins include a number of cell death-promoting factors including cytochrome c, AIF, latent forms of caspases (possibly procaspases-2, 3, and 9), SMAD/Diablo, endonuclease G, and the Omi/HtrA2 serine protease 24. On release, cytochrome c activates the cytosolic Apaf-1, which activates the procaspase-9. Caspase 9 then initiates a proteolytic cascade that destroys the proteins of the cytoplasm. Endonuclease G and AIF are transported to the nucleus, where they degrade the chromatin. The mtPTP can be stimulated to open by the mitochondrial uptake of excessive Ca2+, by increased oxidative stress, or by deceased mitochondrial ΔP, ADP, and ATP. Thus, disease states that inhibit OXPHOS and increase ROS production increase the propensity for mtPTP activation and cell death by apoptosis (Figure 2) (241, 242).

Clinical symptoms appear when the number of cells in a tissue declines below the minimum necessary to maintain function. The time when this clinical threshold is reached is related to the rate at which mitochondrial and mtDNA damage accumulates within the cells, leading to activation of the mtPTP and cell death, and to the number of cells present in the tissue at birth in excess of the minimum required for normal tissue function. Given that the primary factor determining cell metabolism and tissue structure is reproductive success, it follows that each tissue must have sufficient extra cells at birth to make it likely that that tissue will remain functional until the end of the human reproductive period, or about 50 years. If the mitochondrial ROS production rate increases, the rate of cell loss will also increase, resulting in early tissue failure and age-related disease. However, if mitochondrial ROS production is reduced, then the tissue cells will last longer and age-related symptoms will be deferred (236, 238, 241) (Figure 3).

Type II diabetes thus involves mutations in energy metabolism genes including the mtDNA and glucokinase; mutations in the transcriptional control elements PPARγ, PGC-1, HNF-1α, HNF-4α, and IPF-1; and alterations in insulin signaling. These seemingly disparate observations can be unified through the energetic interplay between the various organs of the body.

Notorious variability in the presentation of mitochondrial disease in the infant and young child complicates its clinical diagnosis. Mitochondrial disease is not a single entity but, rather, a heterogeneous group of disorders characterized by impaired energy production due to genetically based oxidative phosphorylation dysfunction. Together, these disorders constitute the most common neurometabolic disease of childhood with an estimated minimal risk of developing mitochondrial disease of 1 in 5000. Diagnostic difficulty results from not only the variable and often nonspecific presentation of these disorders but also from the absence of a reliable biomarker specific for the screening or diagnosis of mitochondrial disease. A simplified and standardized approach to facilitate the clinical recognition of mitochondrial disease by primary physicians is needed. With this article we aimed to improve the clinical recognition of mitochondrial disease by primary care providers and empower the generalist to initiate appropriate baseline diagnostic testing before determining the need for specialist referral. This is particularly important in light of the international shortage of metabolism specialists to comprehensively evaluate this large and complex disease population. It is hoped that greater familiarity among primary care physicians with the protean manifestations of mitochondrial disease will facilitate the proper diagnosis and management of this growing cohort of pediatric patients who present across all specialties.


Increased oxidative stress due to coenzyme Q10 (CoQ10) deficiency leads to an adaptive increase in autophagy [112]. Additionally, it has recently been shown that a defect in mitochondrial protein maintenance can augment autophagy [113]. It follows that a decrease in ROS production will lead to a decrease in the mitochondrial maintenance pathways. This tight regulation of mitochondrial maintenance through ROS is a possible explanation for the disappointing results antioxidants have shown in some human trials.

Food sources: COQ10

CoQ10 is naturally found in high levels in organ meats such as liver, kidney, and heart, as well as in beef, sardines, and mackerel. Vegetarians or vegans who are used to eating these foods should find a suitable alternative. Luckily, vegetable sources of CoQ10 include spinach, broccoli, and cauliflower.


Includes lean meats, poultry, seafood, beans and peas, eggs, and nuts and seeds. Pork, beef, turkey, chicken, fish, shellfish, mushrooms, whole grains and eggs contain high amounts of selenium. Some beans and nuts, especially Brazil nuts, contain selenium.

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