153 Oral - Models of Human Disease I - Diseases with a Neurological Focus
Saturday April 09, 8:15 AM - 8:30 AM

Authors:
Valentina Botero ¹; Bethany Stanhope ⁶; Elizabeth Brown ²; Eliza Grenci ¹; Tamara Boto ³; Scarlet Park ¹; Lanikea King ¹; Keith Murphy ¹; Kenneth Colodner ⁴; James Walker ⁵; Alex Keene ²; William Ja ¹; Seth Tomchik ¹

Affiliations:
1) Scripps Research Institute, Jupiter, FL ; 2) Texas A&M University, College Station, TX; 3) Trinity College Dublin, Dublin, Ireland; 4) Mount Holyoke College, South Hadley, MA; 5) Massachusetts General Hospital, and Harvard Medical School, Boston, MA; 6) Florida Atlantic University, Jupiter, FL

Keywords:
k. developmental disorders; t. other (Metabolism )

Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of complications, including benign tumor formations in the nervous system, altered cellular function, short stature, bone abnormalities, and increased rates of cognitive and developmental disorders. NF1 is caused by mutations in the NF1 gene, which encodes neurofibromin (Nf1), a large protein that functions as a negative regulator of Ras signaling and mediates pleiotropic organismal and cellular functions. Emerging data suggest that Nf1 regulates metabolism: NF1 patients show a reduced body mass index, alterations in metabolites, lower incidences of diabetes, and increased resting energy expenditure. These changes in metabolism may contribute to complications and symptoms associated with NF1. The mechanisms by which Nf1 affects metabolism and energy expenditure are not well understood. Using the Drosophila melanogaster NF1 ortholog, we show that Nf1 regulates metabolic homeostasis via neuronal mechanisms. Drosophila Nf1 is ~60% identical to the human protein and similarly mediates Ras signaling. Our data show that the loss of Nf1 increases metabolic rate via a Ras-GAP-related domain, increases metabolic rate, feeding rate, starvation susceptibility, and alters lipid stores and turnover kinetics. These metabolic alterations map to a restricted subset of neurons in the ventral nervous system and are independent of locomotion and grooming activity. Activation of this restricted neuronal circuit mimics the loss of Nf1 function by increasing metabolic rate when stimulated. These data indicate that Nf1 may regulate changes in neuronal metabolic control, suggest that cellular and systemic metabolic alterations may be a pathophysiological mechanism of NF1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.