Slide 1: NURR1 in Multiple Sclerosis (MS)
Tuesday, September 10, 2024 NUclear Receptor-Related 1 protein (NURR1) in Multiple Sclerosis (MS) Francesca Montarolo, PhD
Slide 2: Agenda
AGENDA ➢ Role of NURR1 – neuro-protective and anti-inflammatory ➢ NURR1 in Multiple Sclerosis (MS) Human data / pregnancy Murine model data ➢ NURR1: a target for DMTs
Slide 3: Role of NURR1: transcription factor of the nuclear receptor 4A subfamily
➢ Role of NURR1 – neuro-protective and anti-inflammatory The Nuclear related protein 1 (NURR1) also called Nuclear receptor 4A2 is a transcription factor belonging to the nuclear receptor 4A subfamily Cheng et al., 2021 Lynne Dershem et al., 2016 NURR1 ligand binding domain (LBD) is close due to the
Slide 4: NURR1 induces neuronal survival and development
➢ Role of NURR1 – neuro-protective and anti-inflammatory NURR1 induces neuronal survival and development modifed by Bruning et al., 2019 In NURR1 gene, polymorphisms and mutations resulting in reduced expression of NURR1 are associated with Parkinson’s disease (PD), where selective degeneration of m
Slide 5: NURR1 anti-inflammatory function and neuro-protection through glial cells
➢ Role of NURR1 – neuro-protective and anti-inflammatory NURR1 exerts anti-inflammatory function by blocking the NF-kB pathway Bensinger et al., 2009 NURR1 exerts neuro-protection through glial cells Kambey et al., 2021
Slide 6: Agenda
AGENDA ➢ Role of NURR1 – neuro-protective and anti-inflammatory ➢ NURR1 in Multiple Sclerosis (MS) Human data / pregnancy Murine model data ➢ NURR1: a target for DMTs
Slide 7: Pregnancy's impact on MS disease activity
➢ NURR1 in Multiple Sclerosis - Human data Pregnancy’s impact on MS disease activity -70% of relapse rate Confraveux et al., 1998 Women with MS experience a substantial reduction of disease activity during pregnancy, particularly in the 3rd trimester relapses worsen further in the post-partum, retur
Slide 8: MS transcript signature: NURR1 reverts to HC value in pregnancy
➢ NURR1 in Multiple Sclerosis - Human data Multiple Sclerosis (MS) transcript signature The gene expression level of NURR1 is down-regulated in treatment naive RRMS blood in comparison to HC, but during pregnancy its imbalance expression returns to HC value Not-pregnant 1st trimester of 2nd trimeste
Slide 9: Genes blocking the pro-inflammatory NF-kB pathway restored in pregnancy
➢ NURR1 in Multiple Sclerosis - Human data Multiple Sclerosis (MS) transcript signature 3 of the 8 genes whose expression level is down-regulated in RRMS and is completely restored to the HC value during pregnancy block the pro-inflammatory pathway of NF-kB Not-pregnant 1st trimester of 2nd trimeste
Slide 10: NURR1 expression negatively correlates with relapse rate and EDSS
➢ NURR1 in Multiple Sclerosis - Human data NURR1 gene expression level negatively correlates with relapse rate and EDSS (aggressive MS) EXPRESSION LEVEL NURR1 expression Clinical worsneing NURR1 Gilli et al., 2010, 2011 Lower levels of NURR1 expression correlate with increased probability of initiat
Slide 11: NURR1 down-regulated in treatment naive RRMS versus HC
➢ NURR1 in Multiple Sclerosis - Human data NURR1 gene expression level is down-regulated in treatment naive RRMS in comparison to HC Gilli et al., 2010, 2011, Navone et al., 2014, Montarolo et al., 2019
Slide 12: NURR1 expressed in human MS brain tissue, correlates with neuronal density
➢ NURR1 in Multiple Sclerosis - Human data NURR1 is expressed human MS brain tissue, and its expression correlates with neuronal cell density == == Higher expression of NURR1 found in the high neuronal density area === Neuro-protective role
Slide 13: Agenda
AGENDA ➢ Role of NURR1 – neuro-protective and anti-inflammatory ➢ NURR1 in Multiple Sclerosis (MS) Human data / pregnancy Murine model data ➢ NURR1: a target for DMTs
Slide 14: NURR1 activation delays EAE onset
➢ NURR1 in Multiple Sclerosis – Murine model data VEHICLE IP7e AXONAL LOSS VEHICLE IP7e DEMYELINATION Induced Experimental Autoimmune Encephalomyelities VEHICLE IP7e (EAE) model of inflammatory demyelination in INFILTRATES C57Bl/6 female mice VEHICLE IP7e The activation of NURR1 delays the onset of
Slide 15: NURR1 deficiency anticipates EAE onset
➢ NURR1 in Multiple Sclerosis – Murine model data Induced Experimental Autoimmune Encephalomyelities (EAE) model of inflammatory demyelination in heterozygous NURR1-KO female mice The deficiency of NURR1 anticipates the onset of the EAE (MOG35-55-chronic model)
Slide 16: Take home message (I)
TAKE HOME MESSAGE (I) ➢ NURR1 expression level is down-regulated in the immune cells of RRMS compared to HC (i.e. female and male - whole blood, PBMCs, CD4+ T cells, monocytes) ➢ Lower levels of NURR1 expression are present in the most active and aggressive MS forms ➢ NURR1 activation delays the ons
Slide 17: Agenda
AGENDA ➢ Role of NURR1 – neuro-protective and anti-inflammatory ➢ NURR1 in Multiple Sclerosis (MS) Human data / pregnancy Murine model data ➢ NURR1: a target for DMTs
Slide 18: NURR1: a target for DMTs
NURR1: a target for DMTs September 2 , 2024 Limitations in the search for NURR1 agonists: ✓ High homology with other NR; ✓ LBD with hydrophobic residues ✓ …
Slide 19: NURR1: a target for DMTs
NURR1: a target for DMTs ns ns ns ns ns
Slide 20: NURR1: a target for DMTs
NURR1: a target for DMTs NURR1 a2 or NURRY NH coon Study of the NR4A family gene expression in patients with multiple wo) sclerosis treated with Fingolimod 20 + 5 ate ; a.D.c a.b.c ab 2,5 ab i) P, 2.0 o F. Montarolo*°° @, S. Perga*° @, S. Matte! Keehn 4 Caldano*” @, M. Lo Re”, G. Panzica** @ Europea
Slide 21: NURR1: a target for DMTs
NURR1: a target for DMTs Optimized Nurr1 agonist with nM potency, strong activation efficacy, pronounced preference over the highly related receptors NR4. Nurr1-regulated gene expression in astrocytes
Slide 22: Thanks
Thanks Regional referal MS center (CReSM) of AOU San Luigi Gonzaga, Orbassano, Turin, Italy ➢ Clinical activity to menage MS patients ➢ Clinical neurophysiology ➢ Neurobiology laboratory ➢ Secretary ➢ Psycology ➢ CReSM BioBank