The X factor in neurodegeneration

Voskuhl, Rhonda R.; Itoh, Yuichiro

doi:10.1084/jem.20211488

Cited by 14 publications

(5 citation statements)

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“…Specifically, testosterone has been shown to bind androgen receptors to induce remyelination and can also be protective via its conversion to estradiol by aromatase in the brain (65)(66)(67). Estradiol mediates neuroprotection by activating estrogen receptors alpha (ERα) and/ In humans, the loss of either testosterone with andropause or estradiol with menopause is believed to be deleterious for neurogenerative changes in MS, brain aging, and Alzheimer's disease, as reviewed in Voskuhl and Itoh (18). The difference in timing of andropause and menopause may play a role in men having worse disability progression and more gray matter substructure atrophy than women.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, when women undergo menopause and have loss of estradiol, it is associated with disability worsening (77)(78)(79)(80)(81)(82)(83). Thus, worse disability progression in men compared to women with MS may be age-dependent, e.g., an age when men exhibit effects of andropause but before women undergo menopause (18).…”

Section: Discussionmentioning

confidence: 99%

“…Observations that sex differences extend beyond humans, for example, to female and male mice in the same environment of a vivarium, reveal the importance of biologic effects. Biologic sex differences can be due to differences in sex hormones (estrogen vs. testosterone), sex chromosomes (XX vs. XY), or both (18,19). Findings from the genotype-tissue expression (GTEx) project revealed the pervasiveness of sex differences in gene expression in humans.…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

Itoh,

Stiles

et al. 2023

Front. Neurol.

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IntroductionMultiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, sex differences in neurodegenerative mechanisms are determined in the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE).MethodsNeurons from cerebral cortex tissues of chronic EAE, as well as age-matched healthy control, male and female mice underwent RNA sequencing and gene expression analyses using RiboTag technology. The morphology of mitochondria in neurons of cerebral cortex was assessed using Thy1-CFP-MitoS mice. Oxygen consumption rates were determined using mitochondrial respirometry assays from intact as well as permeabilized synaptosomes.ResultsRNA sequencing of neurons in cerebral cortex during chronic EAE in C57BL/6 mice showed robust differential gene expression in male EAE compared to male healthy controls. In contrast, there were few differences in female EAE compared to female healthy controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology in neurons showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male, but not female, EAE mice demonstrated significantly decreased oxygen consumption rates during respirometry assays.DiscussionCortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

Itoh,

Stiles

et al. 2023

Front. Neurol.

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“…Differences linked to the sex chromosomes can also be associated with the differential imprinting of the genes deriving from maternal or paternal origin (reviewed in [107]), as well as by the dosage of the X-linked genes.…”

Section: Sex Chromosomes' Impact On Brain Sexual Differentiationmentioning

confidence: 99%

Sex and Brain: The Role of Sex Chromosomes and Hormones in Brain Development and Parkinson’s Disease

Terrin

Tesoriere

Plotegher

et al. 2023

Cells

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Sex hormones and genes on the sex chromosomes are not only key factors in the regulation of sexual differentiation and reproduction but they are also deeply involved in brain homeostasis. Their action is crucial for the development of the brain, which presents different characteristics depending on the sex of individuals. The role of these players in the brain is fundamental in the maintenance of brain function during adulthood as well, thus being important also with respect to age-related neurodegenerative diseases. In this review, we explore the role of biological sex in the development of the brain and analyze its impact on the predisposition toward and the progression of neurodegenerative diseases. In particular, we focus on Parkinson’s disease, a neurodegenerative disorder that has a higher incidence in the male population. We report how sex hormones and genes encoded by the sex chromosomes could protect from the disease or alternatively predispose toward its development. We finally underline the importance of considering sex when studying brain physiology and pathology in cellular and animal models in order to better understand disease etiology and develop novel tailored therapeutic strategies.

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“…In a similar vein, sex and gender differences have been a focus of interest in alpha-synucleinopathies in recent years, due to their potential to disentangle sex-specific disease phenotypes, and translate them to develop novel sex-specific therapeutics -known as a 'benchto-bedside' approach (6)(7)(8). According to the Institute of Medicine's Committee on Sex and Gender Differences, sex and gender differences are biological, physiological, and clinical differences between males and females that arise due to environmental factors and biological effects due to sex chromosomes and gonadal hormones (9).…”

Section: Introductionmentioning

confidence: 99%

Sex differences in alpha-synucleinopathies: a systematic review

Raheel,

Deegan,

Di Giulio

et al. 2023

Front. Neurol.

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BackgroundPast research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review, and to critically assess, contemporary evidence on sex and gender differences in alpha-synucleinopathies using a bench-to-bedside approach.MethodsIn this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid.ResultsOne hundred sixty-two studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects.ConclusionFuture studies disentangling the underlying sex-specific mechanisms of alpha-synucleinopathies are urgently needed in order to enable novel sex-specific therapeutics.

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The X factor in neurodegeneration

Cited by 14 publications

References 182 publications

Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

Sex and Brain: The Role of Sex Chromosomes and Hormones in Brain Development and Parkinson’s Disease

Sex differences in alpha-synucleinopathies: a systematic review

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