Brain–body mechanisms contribute to sexual dimorphism in amyotrophic lateral sclerosis

ABSTRACT Amyotrophic lateral sclerosis (ALS) is the most common form of human motor neuron disease. It is characterized by the progressive degeneration of upper and lower motor neurons,

leading to generalized motor weakness and, ultimately, respiratory paralysis and death within 3–5 years. The disease is shaped by genetics, age, sex and environmental stressors, but no cure

or routine biomarkers exist for the disease. Male individuals have a higher propensity to develop ALS, and a different manifestation of the disease phenotype, than female individuals.

However, the mechanisms underlying these sex differences remain a mystery. In this Review, we summarize the epidemiology of ALS, examine the sexually dimorphic presentation of the disease

and highlight the genetic variants and molecular pathways that might contribute to sex differences in humans and animal models of ALS. We advance the idea that sexual dimorphism in ALS

arises from the interactions between the CNS and peripheral organs, involving vascular, metabolic, endocrine, musculoskeletal and immune systems, which are strikingly different between male

and female individuals. Finally, we review the response to treatments in ALS and discuss the potential to implement future personalized therapeutic strategies for the disease. KEY POINTS *

The molecular mechanisms that underlie sex differences in amyotrophic lateral sclerosis (ALS), in particular the higher prevalence and earlier onset in male over female individuals, are

poorly understood. * The disease mechanisms are modulated by age, genetics and environmental factors that interact to produce a wide range of ALS phenotypes with differences in symptom

presentation and disease onset and duration. * Interactions between the nervous systems and peripheral organs and systems that are strikingly different between sexes in terms of molecular

signature and physiology are key to our understanding of sexual dimorphism in ALS. * Harnessing brain–body interactions could allow the identification of biomarkers and offer new avenues for

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CONTENT BEING VIEWED BY OTHERS DISSOCIATION OF DISEASE ONSET, PROGRESSION AND SEX DIFFERENCES FROM ANDROGEN RECEPTOR LEVELS IN A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS Article Open

access 29 April 2021 FEMALE SEX MITIGATES MOTOR AND BEHAVIOURAL PHENOTYPES IN TDP-43Q331K KNOCK-IN MICE Article Open access 05 November 2020 MULTIOMIC ALS SIGNATURES HIGHLIGHT SUBCLUSTERS

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Phenylbutyrate and Ursodoxicoltaurine (Albrioza)_ (CADTH, 2022). Download references ACKNOWLEDGEMENTS The authors are grateful to M. Bankole for the early discussions about this topic, and

to B. Belanger for designing the original figures. Original work in the laboratories of the authors is supported by grants from the Canadian Institutes of Health Research (CIHR, to K.A.S.

(FRN148380) and M.D.N. (FRN159591)), the K-Brain Project of the National Research Foundation (NRF, to S.H.K. (RS-2023-00265515)), the Krembil Foundation (to M.D.N.), the CIHR/International

Development Research Centre (CIHR/IDRC 109927 to G.P.), the ALS Society of Canada (to M.D.N. and G.P.), the Barry Barrett Foundation (to M.D.N. and G.P.) and the Rose Family Foundation (to

M.D.N. and G.P.). S.S.L. was a recipient of an Alberta Graduate Excellence Scholarship, a CIHR Master’s Scholarship, a Faculty of Graduate Studies Master’s Research Scholarship from the

University of Calgary, and a Donald Burns and Louise Berlin Graduate Award in Dementia from the Hotchkiss Brain Institute. S.M.J. was a recipient of an Alberta Graduate Excellence

Scholarship and Spinal Cord, Nerve Injury & Pain Scholarship from the University of Calgary Hotchkiss Brain Institute. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Hotchkiss Brain

Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Sarah M. Jacob, Sukyoung Lee, Keith A. Sharkey, Gerald Pfeffer & Minh Dang Nguyen * Department of

Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Sarah M. Jacob, Sukyoung Lee, Gerald Pfeffer & Minh Dang Nguyen * Department of Cell

Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Sukyoung Lee & Minh Dang Nguyen * Department of Biochemistry and Molecular Biology,

Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Sukyoung Lee & Minh Dang Nguyen * Department of Neurology, Hanyang University Hospital, Seoul, South Korea

Seung Hyun Kim * Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Keith A. Sharkey * Department of Physiology and

Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Keith A. Sharkey * Department of Medical Genetics, Cumming School of Medicine, University of

Calgary, Calgary, Alberta, Canada Gerald Pfeffer Authors * Sarah M. Jacob View author publications You can also search for this author inPubMed Google Scholar * Sukyoung Lee View author

publications You can also search for this author inPubMed Google Scholar * Seung Hyun Kim View author publications You can also search for this author inPubMed Google Scholar * Keith A.

Sharkey View author publications You can also search for this author inPubMed Google Scholar * Gerald Pfeffer View author publications You can also search for this author inPubMed Google

Scholar * Minh Dang Nguyen View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.M.J., S.S.L., G.P., S.H.K., K.A.S. and M.D.N. wrote the

manuscript. All authors critically reviewed the manuscript drafts and approved the final manuscript for submission. CORRESPONDING AUTHORS Correspondence to Gerald Pfeffer or Minh Dang

Nguyen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Reviews Neurology_ thanks Pamela McCombe and the

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publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jacob, S.M., Lee, S., Kim, S.H. _et al._ Brain–body mechanisms contribute to sexual

dimorphism in amyotrophic lateral sclerosis. _Nat Rev Neurol_ 20, 475–494 (2024). https://doi.org/10.1038/s41582-024-00991-7 Download citation * Accepted: 07 June 2024 * Published: 04 July

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