How redefining 'normal' iron levels could help women's health
Genetics Suggest Link Between ALS And Parkinson's Disease
People with rare genetic variants linked to degenerative brain disorders like Parkinson's disease are at increased risk of developing ALS, a new study finds.
Further, having these genetic variants increases the risk of a person having faster-progressing ALS (amyotrophic lateral sclerosis) and dying earlier, researchers found.
The strongest link was with Parkinson's disease, results show. Those with genes associated with Parkinson's had a 3.6 times greater risk of developing ALS.
"Our findings broaden the understanding of the genetic overlap between ALS and these other disorders by focusing on rare variants instead of common genetic factors," said lead investigator Dr. Maurizio Grassano, a postdoctoral researcher and neurologist at the ALS Center at the University of Turin in Italy.
"Although identifying these variants may not change treatment, the knowledge can help physicians personalize management of those patients," Grassano.
This is the first study to tie ALS, also known as Lou Gehrig's disease, to genetic variants associated with other degenerative brain disorders, the researchers noted.
For the study, researchers analyzed the genetics of 791 people with ALS and 757 healthy people, looking for the presence of 153 genes associated with degenerative brain diseases.
About 18% of the ALS patients carried at least one high-impact gene variant, and 11% had a mutation that hadn't previously been discovered, researchers found.
By comparison, 14% of the healthy people had a gene variant and 7% had a novel mutation.
This suggests that people with ALS have a greater chance of carrying gene mutations associated with other brain diseases, which might have increased their risk of developing ALS, researchers said.
Overall, people who have one of these gene variants have a 30% higher risk of developing ALS. If their mutation hadn't previously been discovered, their risk rose to 80%.
The findings were presented Monday at the American Neurological Association's annual meeting in Orlando, Fla. Such research should be considered preliminary until published in a peer-reviewed journal.
The results suggest that ALS and other degenerative brain diseases work in similar ways.
"In this era of extensive genetic testing, it has become increasingly likely that variants in genes will be detected that are not directly linked to the primary diagnosis," Grassano said in a meeting news release. "These insights will help inform future research on diagnosing and treating this devastating disease."
More information: The ALS Association has more on ALS.
2024 HealthDay. All rights reserved.
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The Role Of Epigenetics In Human Disease
Understanding epigeneticsEpigenetics and developmentEpigenetics and diseaseEpigenetics and lifestyleReferencesFurther reading
Epigenetics plays a critical role in human health by regulating gene expression without the direct modification of DNA sequence. Aberrant epigenetic modifications mediated by changes in DNA and histone methylation and acetylation patterns, in addition to non-coding RNAs, can disrupt normal cellular function and lead to chronic conditions such as cancer and neurological disorders.
Image Credit: VectorMine/Shutterstock.Com
Understanding epigeneticsEpigenetic modifications induce or suppress gene expression without altering the DNA sequence.1 Such modifications include DNA methylation, post-translational histone modifications, and gene expression regulation by ncRNAs.1
The histone proteins, in conjunction with the chromatin, constitute the nucleosomes.1 When the N-terminal tails of histone undergo acetylation or methylation, alterations in chromatin structure and function are observed, which subsequently impact gene expression.1
A variety of extrinsic and intrinsic environmental factors, including nutrition, exposure to toxins, inflammation, aging, exercise, medication, social stress, and metabolic or hormonal disorders, have been linked to influence epigenetic patterns in germ cells.2
These modifications can then be inherited by subsequent generations.2 When epigenetic modifications are transmitted from parents to their direct offspring, it is referred to as intergenerational epigenetic inheritance.2 When these modifications persist beyond the first generation, it is defined as transgenerational epigenetic inheritance.2
The scientific community continues to debate the existence of transgenerational epigenetic inheritance in mammals.2 However, the postulated mechanisms of epigenetic inheritability involve DNA methylation, which commonly acts to repress gene expression, and histone modifications, which can either activate or repress gene expression but are often context-dependent.1-2
Non-coding RNAs, on the other hand, are involved in both transcriptional and post-transcriptional regulation of gene expression, as well as chromatin remodeling through ncRNA-dependent recruitment of chromatin remodeling complexes.1,3
It is noteworthy that research has demonstrated the capacity of acquired epigenetic signatures at specific regions of the mouse genome to be inherited across generations.1 Additionally, during gametogenesis, not all methylated cytosines (5-mC) in primordial germ cells undergo demethylation; a significant proportion of these epigenetic marks exhibit resistance to complete erasure.1
Image Credit: TarikVision/Shutterstock.Com
Approximately 40% of 5-mC and its derivatives persist following extensive epigenetic reprogramming during meiosis.1 Consequently, sperm and oocytes retain an important part of the parental DNA methylation patterns.1
Epigenetics and developmentDuring human embryogenesis, chromatin undergoes extensive remodeling, altering its accessibility at key developmental stages.4 These changes support gene regulatory network rewiring and the establishment of new developmental programs. Regions gaining accessibility are mainly compromised in promoters, CpG islands, and enhancers.4
Over 8,000 promoters open in zygotes, remaining accessible through preimplantation; these genomic regions are enriched with specific metabolic and biosynthetic functions.4
It is important to note that epigenetics plays a significant role in both embryo development and the development of primordial germ cells (PGC), which are precursors of the embryo.5
During their development, mammalian PGCs undergo a distinctive and comprehensive epigenetic remodeling process, coinciding with their transition toward totipotency.5 It is observed that there are differences in the rates of OXPHOS and glycolysis, as well as sexual dimorphism.5
In order to ensure genomic stability during the differentiation process, certain genomic regions retain higher DNA methylation, resisting global demethylation.5 Histone remodeling involves changes in the methylation patterns of H3K9me2, H3K27me3, and H2A/H4R3me2s. These changes are coordinated to safeguard the genome during the transition to totipotency.5
Gene expression is also affected by ncRNAs that interfere with transcription by modulating chromatin. They play roles in dosage compensation and imprinting, crucial for normal development through epigenetic chromatin state modulation.6
Environmental factors that act during the process of embryogenesis, including dietary intake and exposure to toxins, have the potential to alter the uterine environment and fluid composition.7 This, in turn, can affect epigenetic modifications in embryos, influencing their development and potentially leading to structural and functional alterations in the offspring.7
These changes can impact systems such as the immune and cardiovascular systems.7 The effect of these factors causes important metabolic and endocrine changes that can predispose the fetus to certain postnatal diseases.8 This concept is known as fetal programming.8
Epigenetics and diseaseA variety of studies have highlighted the significant role of environmental factors in influencing epigenetic mechanisms, contributing to the pathophysiology of different diseases.
Exposure to neurotoxins, pesticides, and heavy metals has been shown to alter epigenetic patterns linked to Parkinson's disease (PD).9 These changes include increased histone acetylation and DNA methylation, affecting genes associated with PD such as PINK1, PARK2 and TH.9
Hypermethylated patterns have been identified in tumors, frequently located in gene promoter regions of tumor suppressor genes, in contrast to the overall hypomethylated regions observed in cancer cells.10 These hypermethylation patterns have been linked to the development of breast cancer, liver cancer, prostate cancer, and small-cell bladder cancer.10
Additionally, dysregulation of histone deacetylases has also been observed in various cancers, as well as the influence of ncRNAs effect on the expression of protooncogenes like c-Myc in colorectal cancer (CRC).10
Epigenetics plays a crucial role in major depressive disorder and schizophrenia research, with DNA methylation significantly influenced by environmental stressors like childhood adversity.11
These stressors lead to lasting methylation changes, affecting neuroendocrine responses, neuroplasticity, neurotransmission, and neural development in both brain and peripheral tissues.11
EpigeneticsPlay
Histone modifications, especially lysine acetylation, are linked to stress responses and antidepressant effects in depression.11 Additionally, ncRNAs, including circRNAs, miRNAs, and lncRNAs, regulate gene expression, impacting synaptic transmission, insulin resistance, immune responses, and inflammation in these disorders.11
Epigenetics and lifestyleDiet, exercise, and stress significantly impact the epigenome by influencing DNA methylation, histone modifications, and ncRNAs.12
A healthy diet and regular exercise promote beneficial epigenetic changes, such as DNA demethylation and histone modifications, which can help prevent chronic diseases like cancer, diabetes, and cardiovascular disorders.12
Conversely, chronic stress can lead to detrimental epigenetic changes, contributing to disease progression.12 Early-life nutrition is crucial for inducing lifelong epigenetic modifications, while regular physical activity and stress management are essential for maintaining positive epigenetic health.12
Epigenetic therapies hold promise for treating diseases, including cancer and neurodegenerative disorders.13 The reversible nature of the epigenome allows for reprogramming through environmental and pharmacological interventions, enhancing therapeutic strategies.13
However, ethical implications, such as privacy concerns and potential discrimination based on epigenetic profiles, necessitate careful consideration in research and clinical applications, emphasizing the need for equitable access and public policy measures.14
ReferencesXX Marks The Spot: Addressing Sex Bias In Neuroscience
Neuroscience emerged as a defined discipline more than half a century ago, enthralling scientists to study the most enigmatic organ: the brain. Researchers explored animal models and probed the mechanisms behind behavior, cognition, and neurological disorders. As their understanding of the brain expanded, so did the sex gap.
Sex differences extend well beyond reproductive organs and hormones.1 For many neurological and psychiatric diseases, sex-linked differences affect disease prevalence and response to intervention.2,3
Many endpoints do not change across the estrous cycle, but the neuroscience field went male, male, male, and females just dropped out completely.
—Margaret McCarthy, University of Maryland
Historically, most researchers believed that the preferential model, focused on male humans, animals, and cells, was a no-brainer. "Nobody said to include females unless you were specifically asking questions about sex differences," said Rebecca Shansky, a neurobiologist at Northeastern University. This bias stemmed from a seemingly pragmatic view that male data was less fussy and variable, while female data contained higher variability due to the estrous cycle.4 It was not until a string of studies in the mid-1990s rattled researchers' beliefs about the brain.
A Call to Explore Sex as a Biological VariableIn the early 1990s, neuroscientist Bruce McEwen and his group at The Rockefeller University published a series of studies that showed how estradiol, a major female sex hormone, modulated the density of pyramidal cell synapses in the rat hippocampus throughout the estrous cycle.5,6 "It was like a bomb going off in the field because the hippocampus is not involved in reproduction," remarked Margaret McCarthy, a neuroscientist at the University of Maryland who studies sex differences in the developing brain. Pyramidal cells are involved in motor function, memory, and learning. These findings demonstrated that gonadal hormones were not solely relevant for reproduction, but they could alter an adult rat's brain.7 "At first, nobody would believe it. Synapses were supposed to be permanent, and we didn't consider the brain to be plastic then; it was immutable."
Further breakthroughs in hippocampal research highlighted sex differences. However, many researchers continued to believe that excluding female subjects would reduce or eliminate experimental variability. While these biases were not intentionally malicious, the lack of female representation remained a significant concern in the field. This gap drastically limited researchers' understanding of diseases and led to a call for inclusion to rectify this long-standing imbalance of sex representation in biological research.
Rebecca Shansky, neurobiologist at Northeastern University, is a vocal advocate for including both sexes in research.
Vivika Sheppard
In 1993, in a major step forward against sex-biased research, the United States Congress passed the National Institutes of Health (NIH) Revitalization Act, mandating the inclusion of women in clinical trials. This spurred researchers to tackle the road less traveled to redefine the narrative on sex bias: female animals.
"If you believe in science, you should practice science according to the data that we have. This is what I have really been trying to communicate to my peers over the last 10–15 years," remarked Shansky. "Many of these assumptions that are baked into how we think science is going to work are not true, and we should take a minute to introspect on where those biases come from."
To debunk the belief that the estrous cycle rendered female animals more variable in behavioral and neurological outcomes, researchers conducted studies in mice and rats demonstrating that female animals are not more variable than male animals.8-10 "This variability depends on the input, such as housing conditions and even dominance hierarchies," said McCarthy. "Many endpoints do not change across the estrous cycle, but the neuroscience field went male, male, male, and females just dropped out completely."
While clinical trials began including women, this representation did not extend to basic research for another quarter of a century. It was not until 2016 that another major milestone for sex inclusion in basic research emerged to address the sex imbalance. The NIH enforced the "Sex as a Biological Variable" (SABV) research policy, which mandated that sex be factored into research designs, analyses, and reporting in human and animal studies across biomedical research when applicable. This was a deliberate approach to turn the dial towards equitable representation in understanding biological differences and shaping precision medicine.
However, the NIH mandate was met with mixed opinions.11 While many lauded the policy, some researchers remained reluctant to incorporate female models into their work and raised concerns about the increase in experimental durations and variability. Despite this reluctance, the next question many researchers sought to answer was whether this mandate truly alleviated sex bias in neuroscience studies.
Continue reading below...
News & Opinion
Females Gain Ground as Biomedical Research Subjects
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Bridging the Sex Bias GapSex differences are crucial for understanding the brain, yet neuroscience has long favored male models, skewing insights and clinical outcomes. Now, researchers integrate sex as a biological variable in their studies, paving the way for more balanced and inclusive neuroscience research.
1990s: Historically, most of the basic research and clinical studies predominantly focused on male models (humans, animals, and cells). It wasn't until 1993 that the U.S. Congress passed a law in requiring inclusion of women in National Institutes of Health (NIH)-sponsored clinical trials. However, this policy failed to encourage the same standards in basic research.
Early 2000s: The field was influenced by a long-standing belief: fluctuating hormones of the estrous cycle complicated female studies. However, studies showed that female mice and rats were not more variable in non-neurological and neurological outcomes than male animals. This led to a call for female animal inclusion scientific experiments, as neuroscience had a stark sex gap due to male-focused studies.
Late 2010s: In 2016, the NIH enforced the "Sex as a Biological Variable" (SABV) policy, requiring sex to be factored into research designs, analyses, and reporting in biomedical research when applicable. More researchers incorporated female animals, rodents and nonhuman primates, and cell lines, such as induced pluripotent stem cells, to better understand sex differences in neurological disease.
2016–Present: Since SABV, the number of neuroscience studies including both sexes significantly increased. Now, researchers are reframing their analyses of female data to better understand biological differences and shape developing therapeutics.
See full infographic: WEBPDF Exploring the Nuances of Sex as a Biological VariableTo assess the extent of male bias in neuroscience and biomedical research, a meta-analysis conducted in 2009 found that a vast majority did not use both sexes.12 In follow-up analyses examining the number of studies that included both sexes between 2009–2019, with SABV solidly in place, neuroscience greatly benefitted as the research papers incorporating both sexes steadily increased by roughly 30 percent compared to 2009.13,14
A lot of the things that we just kind of assumed would be the same in basic neuroscience are turning out not to be true. That's an exciting point to be at in terms of discovery because we're really blowing up established dogmas about how the brain works.
—Rebecca Shansky, Northeastern University
However, further breakdown of the studies showed that while most papers included both sexes, with a majority using rodents, only 19 percent included studies using an optimal design for finding possible sex differences, and only five percent included sex as a discovery variable.
This oversight is significant as there is a clear pattern for sex-specific prevalence rates for various mental and physical disorders and differences in behavioral responses to stress, pain, and fear.15-17 While the mandate tipped the scale to include female cohorts, there is still room for improvement in updating researchers' experimental designs. For instance, Shansky who studies sex differences in rats' responses to fear, believes that there is much work to be done in terms of validating models.18,19 "Males may express that they have a memory or that they are aggressive, stressed, or sad with a certain repertoire of behaviors that females don't do," said Shansky. "So, if you're just throwing a female into a male-derived test and looking for the same behavior, it's not necessarily going to tell you what you want to know, and that behavior could mean something else and that's something to explore."
Studying sex differences may also reveal no differences. "Finding no differences is just as important and just as interesting, but the truth is, they don't get as much attention," said McCarthy. She studies the reproductive system and reproductive behavior, naturally comparing males and females, but she is also interested in how the brain develops differently in male and female rats.20 While male and female brains share commonalities in the fundamental parameters of brain development, they can differ in the sizes of certain brain regions or the number and types of synapses.21 Beyond these macro and micro differences, male and female brains can diverge due to hormonal influences.22 Researchers have identified epigenetic contributions and differences in responses to psychological or pathogenic stresses.23,24
Margaret McCarthy, a neuroscientist at the University of Maryland, studies sex differences in the developing brain.
Margaret McCarthy
While many neuroscientists examine sex differences in mice and rats, nonhuman primate models are even more underserved in examining sex differences. In Alzheimer's disease (AD), two-thirds of affected individuals are women. Researchers employ transgenic mouse models to develop abnormal proteins that mimic AD. However, Agnès Lacreuse, a primatologist at the University of Massachusetts Amherst, prefers nonhuman primate models as their genetic makeup, brain, behavior, and aging processes more closely resemble those of humans. However, these studies can be cost prohibitive, making it even more difficult to account for a balanced sex comparison.
Lacreuse studies cognitive aging in marmosets, which live around 10–12 years and are good candidates for longitudinal studies as they naturally develop neuropathology relevant to AD. Like humans, she found that aging marmosets displayed intra-individual variability in aging pathologies, such as cognition, neurodegeneration, and neuronal aging. Female marmosets experienced cognitive decline earlier and steeper than male marmosets.25
"Even though the marmoset is not a mini human, they are similar and different to humans in many ways. So, what is important is to do comparative studies between different species of primates, including humans, to better understand how and why these differences exist and their mechanisms," remarked Lacreuse.
Exploring Sex Differences in Cell LinesWhile SABV addressed sex bias concerns in human and animal studies, it posed challenges in the context of cell lines. Cell lines derived from reproductive tissue inherently denote their sex, yet the sex of other cell lines often remained unspecified in research. Researchers explored the advancement of cell lines, notably the emergence of mouse and human induced pluripotent stem cells (iPSCs) as promising models for studying neurological disease.26-28 With four transcription factors, researchers could convert somatic cells into pluripotent stem cells, bypassing the need for embryos and the controversy surrounding their use, and readily create patient-specific cell lines from both male and female donors.29 Therefore, iPSCs emerged as a key focal point for implementing SABV, to ensure a more balanced representation of cells from both sexes in rigorous studies.
Agnès Lacreuse, a primatologist at the University of Massachusetts Amherst, studies cognitive aging and women's health issues in marmosets.
Evan Yeadon
For Tracy Young-Pearse, a stem cell neuroscientist at Harvard University and Brigham and Women's Hospital, using iPSCs in a dish was paradigm-shifting for neurological disease.30 She investigates sex differences primarily in the context of AD and the genetic factors driving heterogenetic phenotypes.
"[With iPSC models], we can capture the human genome from many different types of people, and we can understand how genetic variants, even when they're not super strong or fully penetrative mutations, interact with one another to affect cell biology in different molecular pathways," explained Young-Pearse.
iPSCs provide context for studying male versus female differences in mice and humans. Researchers can explore roughly 70 AD-associated loci and the differences in gene and protein levels on sex and somatic chromosomes, as well as study hallmark signs of amyloid beta (Aβ) plaques and tau tangles in the brain.
The varying degrees of accumulation between Aβ plaques and tau tangles provide a foundation for making lines from various people who had different trajectories and ages of onset. "What's really exciting is that we can not only understand those molecularly, but we can understand and disentangle those different molecular roads by using these cells in a dish," said Young-Pearse.
The NIH also invested in these cell models for studying neurological disease through initiatives such as the iPSC Neurodegenerative Disease Initiative (iNDI) to generate hundreds of iPSC genetic variants to study different forms of dementia.31 The project employed various gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems.32 Currently, iNDI mainly consists of iPSCs from male donors, due to the concern that random X-chromosome inactivation could skew gene expression in female lines. However, the project aims to include a more robust representation of female cell lines moving forward.
Tangentially, a team of scientists at the Hadassah University Medical Center developed a line of human iPSCs (hiPSCs) from one donor with an unusual case of Klinefelter syndrome to study sex differences without confounding variables such as interpersonal differences.33 This disorder results in an additional X chromosome in males (XXY), and researchers leveraged this unique model to generate hiPSC lines with different sex chromosome makeups (XX, XY, X0, and XXY) that were otherwise genetically identical. The use of this model provides a promising platform for better understanding the similarities and differences between the sexes in a wide range of health and disease contexts in neuroscience and beyond.
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News & Opinion
Male and Female Stem Cells Derived from One Donor in Scientific First
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Looking Ahead with SABV 2.0Nearly ten years after the SABV mandate, researchers reflect on where neuroscience research stands in terms of equitable representation and accurate interpretation of female findings to better understand biological differences and shape precision medicine. McCarthy believes that with the 10th anniversary of SABV approaching in 2026, it would be beneficial to revisit its requirements and possibly develop SABV 2.0.34
"It's a paralyzing and controversial subject, but it's very dangerous to think that we should not study sex differences," remarked Lacreuse. As sex can influence multiple aspects of brain behavior and disease, "It is really important to include women in all studies, and while our studies speak about differences, it doesn't mean that one is better than the other."
Tracy Young-Pearse, a stem cell neuroscientist at Harvard University and Brigham and Women's Hospital, studies sex differences in neurologic diseases with iPSC models.
Brigham and Women's Hospital
For Shansky, a balanced representation of female animals is only one aspect of improvement, and reevaluating how data is interpreted between male and female animals is another crucial consideration. She remains optimistic about continuously improving tools. "For the next wave of the behavioral neuroscience renaissance, all these machine learning tools do careful and high-resolution behavior analysis, and that's the next step that's going to allow us to better figure out what we should be looking at. It's an evolving scene."
While sex inclusion was just one checkbox on the laundry list of improving neuroscience research, there are still improvements to be made. Aside from data analysis, the next wave of progress may also create a more complex model such as gender identity. "One of the things we need to work on now is incorporating those environmental factors that affect health and disease that's relevant in terms of male versus female. That can really help propel us forward in having good human experimental systems for understanding responses to therapeutics," said Young-Pearse.
Many are optimistic that SABV continues to be viewed as a boon rather than a burden and that the mandate will steadily reap benefits at the basic and translational levels with continued improvements. "A lot of the things that we just kind of assumed would be the same in basic neuroscience are turning out not to be true. That's an exciting point to be at in terms of discovery because we're really blowing up established dogmas about how the brain works," said Shansky.
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