In a groundbreaking new study that sheds light on the enigmatic mechanisms underpinning neurodegenerative processes, researchers have uncovered a compelling link between estrogen-related receptor gene expression and sex-specific patterns of cortical atrophy in isolated REM sleep behavior disorder (iRBD). This discovery, recently published in Nature Communications, has the potential to redefine our understanding of sex differences in neurodegeneration and pave the way for personalized therapeutic interventions. The findings intricately map the molecular landscape associated with iRBD, a condition increasingly recognized as a prodromal phase of alpha-synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies.
Isolated REM sleep behavior disorder is a fascinating condition characterized by the disruption of normal muscle atonia during REM sleep, resulting in dream enactment behaviors that can range from benign limb movements to violent motor activity. While iRBD itself represents a unique clinical syndrome, extensive research has identified it as a harbinger of neurodegenerative disorders, occurring years before the onset of classical motor and cognitive symptoms. The challenge has been to clarify why and how distinct neurodegenerative trajectories differ between males and females, a question now tackled by exploring gene expression dynamics associated with estrogen-related receptors (ERR).
Filiatrault and colleagues approached this investigation with a robust, multidimensional methodology, combining advanced neuroimaging with transcriptomic analyses. Their work began by quantitatively assessing cortical atrophy patterns in men and women diagnosed with iRBD, revealing marked sex differences in both the distribution and severity of regional cortical thinning. These differences sparked an exploration into molecular correlates, focusing specifically on ERR gene expression – a cluster of nuclear receptors known for their regulatory roles in energy metabolism and mitochondrial function, but whose involvement in neurodegeneration remains underappreciated.
The cortical atrophy observed in men chiefly involved dorsal frontoparietal regions, while women exhibited greater vulnerability in orbitofrontal and cingulate cortices. These neuroanatomical disparities suggest sex-specific vulnerabilities potentially influenced by intrinsic genetic and hormonal factors. By leveraging publicly available gene expression datasets mapped onto cortical regions, the researchers identified a significant association between areas exhibiting greater atrophy and differential expression of estrogen-related receptor genes. This compelling link posits ERRs as pivotal modulators of neurodegenerative vulnerability in iRBD, mediated by their influence on cellular bioenergetics and synaptic homeostasis.
ERRs, although inactive by classical estrogenic ligands, are orphan nuclear receptors intricately involved in the regulation of mitochondrial biogenesis and oxidative phosphorylation pathways crucial for neuronal survival. Their capacity to govern cellular metabolism renders them prime candidates in modulating neuronal resilience or susceptibility to degenerative insults. Filiatrault et al.’s finding that ERR gene expression correlates with sex-specific cortical atrophy intensifies the hypothesis that metabolic dysregulation is a driving force behind neurodegeneration in iRBD, potentially modulated by sex-dependent genetic and epigenetic regulation.
The study’s interplay between neuroimaging and transcriptomics marks a leap forward in precision neurobiology. The cortical regions identified not only coincide with the known neurocircuitry implicated in sleep regulation and motor control but also overlap with brain areas affected in later stages of alpha-synucleinopathies. Therefore, these data underscore the critical window presented by iRBD, a phase when neurodegenerative changes commence silently, and interventions tailored to sex-specific molecular profiles could forestall progression or ameliorate disease impact.
What amplifies the significance of these findings is the translational promise embedded within ERRs as therapeutic targets. Modulating ERR activity pharmacologically could recalibrate neuronal metabolic fluxes, enhancing resilience against the mitochondrial dysfunction and oxidative stress long recognized as central to neurodegenerative pathology. By unraveling the sex-dependent landscape of ERR expression and cortical vulnerability, this research opens the possibility for sex-tailored treatment strategies that harness receptor biology for neuroprotection in at-risk populations.
Intriguingly, the role of estrogen signaling in neurodegeneration has long been a topic of intense inquiry, with fluctuating hormone levels across the lifespan implicated in differential disease vulnerabilities between men and women. ERRs, by virtue of their structural ties to estrogen receptors yet ligand-independent operation, provide a unique nexus in understanding how estrogenic pathways intersect with metabolic regulation in the brain. This innovative angle not only bridges endocrinology and neurodegeneration but also invites a reexamination of sex hormones’ indirect and direct effects on neuronal health.
The research team’s comprehensive cohort included a balanced representation of sexes and meticulous clinical characterization, enhancing the validity of the observed associations. Additionally, their analytical framework incorporated rigorous correction for confounders such as age and disease duration, bolstering confidence that ERR gene expression genuinely accounts for differential atrophy patterns rather than being an epiphenomenon. This meticulousness sets a benchmark for future explorations into sex-related molecular neurobiology.
Beyond immediate clinical implications, these discoveries also serve to highlight the crucial importance of considering sex as a biological variable in neuroscience research broadly. Historically, female subjects have been underrepresented in studies of neurodegeneration, obscuring critical sex-specific pathways that could unlock novel diagnostic and therapeutic avenues. Filiatrault et al.’s findings champion the inclusivity of sex-diverse cohorts and advocate for gene expression analyses intricately tailored to unravel the molecular underpinnings that drive divergent disease phenotypes.
Moreover, illuminating the connections between ERR expression and cortical atrophy patterns enriches our comprehension of how neuronal circuits degrade differently in men and women. This nuanced understanding is vital as the field moves towards biomarker development that can predict disease progression with high fidelity, ideally before irreversible neurodegenerative damage occurs. Imaging-genetic signatures centered on ERRs could form the basis of such predictive models, guiding clinicians in risk stratification and personalized interventions.
The intersection of sleep medicine, neurogenetics, and sex-based neuroscience heralded by this study is poised to galvanize a wave of follow-up research. Key questions now revolve around the precise mechanistic pathways through which ERRs influence neuronal survival, how these intersect with classical neurodegenerative proteins such as alpha-synuclein, and whether ERR modulation can be leveraged therapeutically in preclinical models. Equally critical is to explore how hormonal fluctuations interact with ERR gene regulation across the lifespan and disease course.
In summary, the work spearheaded by Filiatrault and colleagues represents an important stride in decoding the complex biological tapestry that defines neurodegeneration in isolated REM sleep behavior disorder. Their elucidation of estrogen-related receptor gene expression as a mediator of sex-specific cortical atrophy not only deepens our understanding of brain vulnerability but also charts a promising course towards precision medicine. The potential to innovate targeted, sex-specific therapies that hinge on metabolic and transcriptional regulators like ERRs may transform the prognosis for individuals facing the looming shadow of neurodegenerative diseases.
As the neurobiology community digests these findings, there is palpable excitement about the broader implications beyond iRBD alone. Sex-dependent mechanisms involving ERRs could resonate across a spectrum of neurodegenerative conditions, compelling a paradigm shift in how we study, diagnose, and treat brain disorders. This landmark study acts as a clarion call to integrate molecular sex differences into the core of neurodegenerative research and clinical care.
The emergent narrative underscores the critical nature of integrating multi-omics data with high-resolution imaging to capture the biological nuances of disease. By illuminating distinct pathological trajectories through the lens of sex and gene expression profiles, researchers inch closer to unraveling the elusive codes that govern neurodegeneration. The potential to transform these insights into clinical innovations offers hope in a domain often marked by therapeutic stagnation.
Ultimately, the work of Filiatrault et al. is a testimony to the power of collaborative, multidisciplinary science. Bridging genomics, neuroimaging, and clinical neurology, their study exemplifies the holistic approach required to confront the complexities of brain disorders. As neurodegenerative diseases continue to impose a growing global burden, such pioneering research provides invaluable beacons guiding future investigation and treatment paradigms.
Subject of Research:
Sex differences in cortical atrophy and their association with estrogen-related receptor gene expression in isolated REM sleep behavior disorder.
Article Title:
Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder.
Article References:
Filiatrault, M., Ayral, V., Tremblay, C. et al. Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder. Nat Commun 16, 9016 (2025). https://doi.org/10.1038/s41467-025-63829-w
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