Lee SD, Priest C, Bjursell M, Gao J, Arneson DV, Ahn IS, Diamante G, van Veen JE, Massa MG, Calkin AC, Kim J, Andersén H, Rajbhandari P, Porritt M, Carreras A, Ahnmark A, Seeliger F, Maxvall I, Eliasson P, Althage M, Åkerblad P, Lindén D, Cole TA, Lee R, Boyd H, Bohlooly-Y M, Correa SM, Yang X, Tontonoz P, & Hong C. IDOL regulates systemic energy balance through control of neuronal VLDLR expression. Nature Metabolism 1, 1089-1100 (2019).
Role: stereotaxic injections to the ventrolateral portion of the ventromedial hypothalamus in mice
Liver X receptors limit cellular lipid uptake by stimulating the transcription of inducible degrader of the low-density lipoprotein receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose tissue, endothelium, intestine, and skeletal muscle) but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to the control of metabolism. Finally, we identified very low-density lipoprotein receptor (VLDLR) rather than low-density lipoprotein receptor (LDLR) as the primary mediator of the effects of IDOL on energy balance. These data identify a role for the neuronal IDOL–VLDLR pathway in metabolic homoeostasis and diet-induced obesity.
Massa MG*, David C*, Jörg S, Berg J, Gisevius B, Hirschberg S, Linker RA, Gold R, & Haghikia H. Testosterone differentially affects T cells and neurons in murine and human models of neuroinflammation and neurodegeneration. Am. J. Pathol. 187, 1613-22 (2017).
Role: study conception and design, experimental execution, manuscript preparation and submission
The high female-to-male sex ratio of multiple sclerosis (MS) incidence has continuously confounded researchers, especially in light of male patients’ accelerated disease course at later stages of MS. While multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormonal treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. While subcutaneous treatments of testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated the initial course of disease, similar treatment administered therapeutically exacerbated the chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic stage. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiological sex differentials observed in MS disease incidence and course.
Berg J, Mahmoudjanlou Y, Duscha A, Massa MG, Thöne J, Esser C, Gold R, & Haghikia A. The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor. J. Neuroimmunol. 298, 9-15 (2016).
Role: scientific framing, manuscript organization, English language proofing
Though several functional properties of laquinimod have been identified, our understanding of the underlying mechanisms is still incomplete. Since the compound elicits similar immunomodulatory effects to ligands of the aryl hydrocarbon receptor (AhR), we compared the efficacy of laquinimod in experimental autoimmune encephalomyelitis (EAE)-afflicted wild-type and AhR-deficient mice. Laquinimod failed to ameliorate clinical symptoms and leukocyte infiltration in AhR-deficient mice; however, treatment exerted neuroprotection by elevation of brain-derived neurotrophic factor (BDNF) independent of genetic profile. Thus, our data identify the AhR pathway in these mutant mice as crucial for the immunomodulatory, but not neuroprotective, efficacy of laquinimod in EAE.
Massa MG*, Gisevius B*, Hirschberg S*, Hinz L, Schmidt M, Gold N, Prochnow N, & Haghikia A. Multiple Sclerosis Patient-Specific Primary Neurons Differentiated from Urinary Renal Epithelial Cells via Induced Pluripotent Stem Cells. PLoS One 11, e0155274 (2016).
Role: methodology development, figure preparation, manuscript composition and submission
As multiple sclerosis research progresses, it is pertinent to continue to develop suitable paradigms to allow for ever more sophisticated investigations. Animal models of multiple sclerosis, despite their continuing contributions to the field, may not be the most prudent for every experiment. Indeed, such may be either insufficient to reflect the functional impact of human genetic variations or unsuitable for drug screenings. Thus, we have established a cell- and patient-specific paradigm to provide an in vitro model within which to perform future genetic investigations. Renal proximal tubule epithelial cells were isolated from multiple sclerosis patients’ urine and transfected with pluripotency-inducing episomal factors. Subsequent induced pluripotent stem cells were formed into embryoid bodies selective for ectodermal lineage, resulting in neural tube-like rosettes and eventually neural progenitor cells. Differentiation of these precursors into primary neurons was achieved through a regimen of neurotrophic and other factors. These patient-specific primary neurons displayed typical morphology and functionality, also staining positive for mature neuronal markers. The development of such a non-invasive procedure devoid of permanent genetic manipulation during the course of differentiation, in the context of multiple sclerosis, provides an avenue for studies with a greater cell- and human-specific focus, specifically in the context of genetic contributions to neurodegeneration and drug discovery.
Sex Differences in a Novel Node of the Feeding Circuit. Doctorate thesis. In progress. Advisor: Dr. Stephanie M. Correa
Rapid Effects of Testosterone on Responsiveness to Sex Pheromones in Male Carassius auratus. Honors project. Bowdoin College, 2014. Advisor: Dr. Richmond Thompson.
Sex differences in a novel node of the feeding circuit. Presenter (Poster) & Speaker (Invited Lightning Talk), Obesity Week, 2019.
Sex differences in the role of tuberal somatostatin-positive neurons in feeding. Presenter (Poster), Diabetes and Obesity Research Institute (DORI) at USC, 2019.
Differential effects of sex steroid hormones on the chronic and acute phases of experimental autoimmune encephalomyelitis. Presenter (Poster), European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS), 2015.
Rapid estrogenic and androgenic effects on sensory processing in male Carassius auratus. Co-presenter (Poster), Society for Neuroscience (SfN) Faculty for Undergraduate Neuroscience session, 2013.
Rapid androgenic effects on olfactory response to prostaglandin F2α (PGF2α), a conspecific ovulatory pheromone, in Carassius auratus. Presenter (Poster), President’s Science Symposium at Bowdoin College, 2013.