INVESTIGADORES
CARNIGLIA Lila
congresos y reuniones científicas
Título:
HMGB1 inhibition ameliorates HD knock-in mice phenotype
Autor/es:
JULIETA SABA; FEDERICO LÓPEZ COUSELO; JULIETA BRUNO; MATEO PALMIERI; DIEGO RIVAS; LILA CARNIGLIA; DANIELA DURAND; MERCEDES LASAGA; CARLA CARUSO
Reunión:
Congreso; LATBRAIN 2022; 2022
Resumen:
Huntington disease (HD) is a dominant neurodegenerative disease caused by CAG expansion in Huntingtin (Htt) gene with progressive loss of striatal neurons resulting in cognitive impairment and motor dysfunction. HD pathogenic mechanisms have not been elucidated yet. HMGB1 is a nuclear protein released from neurons upon exposure to toxic factors or from activated glial cells, which, once released, can induce inflammation through RAGE, TLR4, and TLR2 receptors. The expression of RAGE and TLR4 was increased in the striatum of HD patients. Glycyrrhizin (GLY) is a natural product that binds to and inhibits HMGB1 release from damaged cells and reduces HMGB1 expression. GLY has neuroprotective effects on traumatic brain injury, neuroinflammation, and Alzheimer’s and Parkinson’s diseases. Moreover, GLY administration improves cognitive function of aging mice. However, HMGB1 participation in HD is unknown. Our goal is to determine HMGB1 role in HD pathogenesis.Four- and eight-month-old (4M and 8M) zQ175 (HD) knock-in female mice but only 8M male HD mice showed motor dysfunction in the open field test. Expression of HMGB1 protein was higher in the striatum of 4M and 8M female HD mice whereas no difference was found in the cortex of the same animals. HMGB1 expression showed decreased levels of HMGB1 in 8M HD male mice cortex but increased levels in 8M HD mice male striatum, indicating that striatal HMGB1 increased expression correlates with motor dysfunction. Also, HD mice exhibited memory deficits at 4M and 8M, as shown by reduced exploration of the novel object in the novel object recognition test. We next tested whether blocking HMGB1 could modify 4M HD mice phenotype. GLY treatment (100 mg/kg ip, administered once a day for 15 days) significantly increased the distance traveled by 4M female HD mice in the open field test. The reduction of the discrimination index, i.e., low preference for the new object, of HD mice in the NOR test was prevented by GLY-treatment, indicating that GLY improves memory function. Moreover, GLY treatment decreased HMGB1 expression in the striatum of male and female HD mice. Thus, our results suggest that HMGB1 is involved in HD pathogenesis and furthermore that GLY treatment may be beneficial for HD.