Nuclear receptor signaling in neurodevelopment and neurodegeneration - Ivan Nalvarte

Our group works within the field of nuclear receptors, a family of transcription factors of very high physiological and pathophysiological significance. They regulate expression of several hundreds of genes and are often activated or inactivated by low molecular weight ligands, e.g. steroid hormones or intermediary metabolites.

Our main focus lies on the neurobiological role of two nuclear receptor (NR) transcription factors that were discovered by Prof. Jan-Åke Gustafsson in our laboratory; the Estrogen receptor beta (ERβ) and the Liver X receptor beta (LXRβ).

illustration of a circle, NR in the middle and arrows pointing to environment, development and so on
NRs are ligand activated nuclear transcription factors. They function downstream of endocrine processes to mediate the response to external and internal stimuli, thereby controlling the expression of genes involved in homeostasis, metabolism, growth and development. Since they often bind low molecular weight ligands they pose promising targets for therapeutic interventions. Our research group study a subset of nuclear receptors, the oestrogen receptors (ER's) and the liver X receptors (LXR's) that are involved in inflammation, metabolism, proliferation and development. Illustration: Ivan Nalvarte

The female sex hormone estrogen has a well-established role in controlling sexual differentiation, maturation and reproduction. Its deregulation during critical life phases may thus affect reproduction, but can also associate with increased risk of developing different neurological diseases that display clear sex differences, such as depression and Alzheimer’s disease. Our group study the molecular underpinnings behind the sex differences in neurological diseases. A primary focus lies on ERβ. In contrast to ERα, which mainly controls neural circuits related to reproduction, ERβ is expressed in brain areas related to cognition and mood, where it appears to be involved in modulating neuroprotection and cognitive behavior.

group photo, people standing
The INA group. From the left: Ivan Nalvarte, Per Antonson, Mohamed Shamekh, Birgitta Lindqvist, Jose Inzunza, Chiara Gabbi, Mukesh Varshney, Aphrodite Demetriou. Not in the photo: Jan-Åke Gustafsson and Ayesha Parjapati. Photo: Belinda Pannagel

Since sex hormone signaling crosstalks with brain cholesterol metabolism, we also study the role of estrogen on pathways associated with LXRβ signaling, an important nuclear receptor of oxysterols (metabolized cholesterol) in the brain. Both ERβ and LXRβ can be selectively targeted by small lipophilic compounds, which may hold great promise in developing new, more personalized, treatment strategies to combat neurological diseases in men and women.

In addition to study the role of sex hormones in the brain, we study nuclear receptor signaling in breast and prostate cancer, metabolism, inflammation, and reproduction.

Group members

Ivan Nalvarte

Group leader, Associate professor
08-524 811 48

Jan-Åke Gustafsson

Professor
+46-(0)8-524 811 46

Per Antonson

Senior researcher
08-524 810 49

Mohamed Shamekh

PhD Student
08-524 811 48

Mukesh Varshney

Researcher

Jose Inzunza

Researcher
08-524 811 01

Birgitta Lindqvist

Lab. technician
073-209 83 12

Aphrodite Demetriou

PhD student

Chiara Gabbi

Other

Heba Ali

PhD student

Selected Publications

Estrogen receptors and the aging brain.
Maioli S, Leander K, Nilsson P, Nalvarte I
Essays Biochem 2021 Dec;65(6):913-925

Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice.
Li X, Zhong H, Wang Z, Xiao R, Antonson P, Liu T, Wu C, Zou J, Wang L, Nalvarte I, Xu H, Warner M, Gustafsson JA, Fan X
Mol Psychiatry 2021

Motor function deficits in the estrogen receptor beta knockout mouse: Role on excitatory neurotransmission and myelination in the motor cortex.
Varshney MK, Yu NY, Katayama S, Li X, Liu T, Wu WF, et al
Neuroendocrinology 2020 Jan:111(1-2):27-44

Estrogen receptor beta and neural development.
Nalvarte I, Varshney M, Inzunza J, Gustafsson JÅ
Vitam Horm 2021;116():313-326

Sex Stratified Treatment of Neurological Disorders: Challenges and Perspectives.
Nalvarte I
Brain Sci 2020 Feb;10(2):

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.
Warner M, Wu WF, Montanholi L, Nalvarte I, Antonson P, Gustafsson JA
Proc. Natl. Acad. Sci. U.S.A. 2020 Mar;117(9):4902-4909

LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux.
Thomas DG, Doran AC, Fotakis P, Westerterp M, Antonson P, Jiang H, et al
Cell Rep 2018 12;25(13):3774-3785.e4

Estrogen receptor β controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage.
D'Errico F, Goverse G, Dai Y, Wu W, Stakenborg M, Labeeuw E, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 05;115(22):5798-5803

Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells.
Varshney MK, Inzunza J, Lupu D, Ganapathy V, Antonson P, Rüegg J, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 11;114(48):E10428-E10437

Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate.
Wu WF, Maneix L, Inzunza J, Nalvarte I, Antonson P, Kere J, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 05;114(19):E3816-E3822

Prizes/Awards

Selection of prizes awarded to Dr. Ivan Nalvarte:

  • Forska Utan Djurförsök, 2021
  • NIH prime-PI, R01AG065209, 2020
  • STINT Sweden-Chile Network award, 2019
  • Karolinska Institutet funds, 2019, 2021
  • Emil & Wera Cornell’s research foundation, 2016-2020
  • Arne Lundberg’s foundation, 2008
  • KI PhD studentship award (doktorandmånader), 2004

Selection of prizes awarded to Prof. Jan-Åke Gustafsson:

  • Vetenskapsrådet, continuous
  • Cancerfonden, continuous
  • CIMED senior award, 2015
  • The Grand Silver Medal of the Karolinska Institutet, 2011
  • The Grand Nordic Fernström Prize of the University of Lund, 2009
  • Geoffrey Harris Prize, 2009
  • Bristol-Meyers Squibb / Mead Johnson Award for Nutrition Research, 2004
  • Medal from Biomedicum Helsinki, 2004
  • Fred Conrad Koch Award (Endocrine Society USA), 2002
  • Chairman of the Nobel Assembly of the Karolinska Institutet, 2002
  • Foreign Honorary Member of the US National Academy of Sciences, 2002
  • The Söderberg Prize in Medicine, 1998
  • The Anders Jahre Prize, Oslo, 1992

Research Networks

  • CAR - KI network on sex and gender difference in dementia and ageing
  • Neurotoxicity society
  • NIA (NIH) focus area on Sex Differences in AD and ADRD
  • SWACCS, Swedish Academic Consortium on Chemical Safety
  • Swedish 3R academy

Looking for a student project or internship?

We are looking for students interested in an internship or degree project in the field of estrogen signaling in the brain. The project aims at deciphering estrogen receptor beta’s (ERbeta’s) neuroprotective role in Alzheimer’s disease (AD) and why women are more affected by this disease than men. The project involves cell biological and biochemical characterizations of models of AD where ERbeta is activated or lost. Research on the neuroprotective contribution of ERbeta during sensitive periods in life may open up for new preventive and more personalized recommendations to new AD risk groups.

Contact Ivan Nalvarte for more information.

IN
Content reviewer:
Ivan Nalvarte
Sara Bruce
12-05-2023