Abstract
ABSTRACTSevere appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation (C19T) that converts an arginine to a tryptophan (R7W) in the TYRO3 protein tyrosine kinase 3 (Tyro3) gene, which resides within the anx critical interval, as contributing to the severity of anx phenotypes. Our observation that, like Tyro3−/− mice, anx/anx mice exhibit abnormal secondary platelet aggregation suggested that the C19T Tyro3 variant might have functional consequences. Tyro3 is expressed in the hypothalamus and other brain regions affected by the anx mutation, and its mRNA localization appeared abnormal in anx/anx brains by postnatal day 19 (P19). The presence of wild-type Tyro3 transgenes, but not an R7W-Tyro3 transgene, doubled the weight and lifespans of anx/anx mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in Tyro3-transgenic anx/anx mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible in vitro, distribution of R7W-Tyro3 protein differed from that of Tyro3 protein in the cerebellum of transgenic wild-type mice. Thus, R7W-Tyro3 protein localization deficits are only detectable in vivo. Further analyses revealed that the C19T Tyro3 mutation is present in a few other mouse strains, and hence is not the causative anx mutation, but rather an anx modifier. Our work shows that Tyro3 has prosurvival roles in the appetite regulatory circuitry and could also provide useful insights towards the development of interventions targeting detrimental weight loss.
Highlights
IntroductionDetrimental appetite and weight loss are the defining features of the restrictive subtype of the eating disorder anorexia nervosa (ANR) (Kaye et al, 1998, 2000; Walsh and Devlin, 1998), and often accompany a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) (Ahmed et al, 2016), Alzheimer’s disease (AD) (Ringman et al, 2015; Burke et al, 2016; Sergi et al, 2013) and Huntington’s disease (HD) (Petersén et al, 2005; Gabery et al, 2010)
A point mutation in the signal sequence of tyrosine kinase 3 (Tyro3) is associated with the anx phenotype The Tyro3 gene is located within the anx critical interval, which we had refined to a 3.5 Mb region between D2Mit484 and D2Mit3 by using simple sequence length polymorphisms (SSLPs) to analyze 335 progeny (670 meioses) from heterozygous intercrosses on C57BL6/J (n=111) and Mus molossinus/Ei (MOLF/EiJ) (n=224) strain backgrounds (Fig. S1)
This mutation converts an arginine to a tryptophan at the seventh amino acid position, and eliminates an NlaIV restriction site (Fig. 1B), which we used in a polymerase chain reaction (PCR)-based assay to genotype 995 additional animals
Summary
Detrimental appetite and weight loss are the defining features of the restrictive subtype of the eating disorder anorexia nervosa (ANR) (Kaye et al, 1998, 2000; Walsh and Devlin, 1998), and often accompany a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) (Ahmed et al, 2016), Alzheimer’s disease (AD) (Ringman et al, 2015; Burke et al, 2016; Sergi et al, 2013) and Huntington’s disease (HD) (Petersén et al, 2005; Gabery et al, 2010). Appetite and weight loss are linked to poor mood and quality of life in ALS patients and can be major issues for many during late disease progression. In spite of their impact, the neurobiological systems (Kaye et al, 2013) and genetic factors (Shih and Woodside, 2016; Clarke et al, 2012; Pinheiro et al, 2009) that contribute to reduced food intake in ANR remain poorly understood and are likely complex, and have been largely unexplored in neurodegenerative disorders. In brief, loss of hypothalamic NPY/AGRP neurons, increased glutamatergic signaling from the PBN or serotonergic hyperinnervation of the Disease Models & Mechanisms (2017) 10, 581-595 doi:10.1242/dmm.027433 nucleus tractus solitarius (NTS) could individually or together promote pathological appetite and weight loss
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