Roberts, L. D. | bioRxiv Science

bioRxiv2018

Circulating unacylated-ghrelin impairs hippocampal neurogenesis and memory in mice and is altered in human Parkinson’s disease dementia

Blood-borne factors regulate adult hippocampal neurogenesis (AHN) and cognition in mammals, albeit via mechanisms that are poorly understood. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in GOAT-/- mice that lack acyl-ghrelin (AG) but have high levels of UAG, were rescued by treatment with AG. This unexpected finding suggests that the post-translational acylation of ghrelin is an important modulator of neurogenesis and memory in adult mammals. To determine whether this paradigm is relevant to humans we analysed circulating AG:UAG levels in Parkinsons disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients and healthy controls. Uniquely, the ratio of plasma AG:UAG was reduced in the PDD cohort and correlated with cognitive performance. Our results identify UAG as a novel regulator of neurogenesis and cognition, and AG:UAG as a circulating diagnostic biomarker of dementia. The findings extend our understanding of adult brain plasticity regulation by circulating factors and suggest that manipulating the post-translational acylation of plasma ghrelin may offer therapeutic opportunities to ameliorate cognitive decline.\n\nHighlightsO_LICirculating UAG impairs markers of neurogenesis and plasticity\nC_LIO_LIGOAT-/-mice have impaired neurogenesis and spatial memory\nC_LIO_LICirculating acyl-ghrelin (AG) rescues spatial memory deficit in GOAT-/-mice\nC_LIO_LICirculating AG:UAG ratio is reduced in Parkinsons disease dementia\nC_LI

neuroscience↗

bioRxiv2017

The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1

Pharmacological inhibition of uncontrolled cell growth with small molecule inhibitors is a potential strategy against glioblastoma multiforme (GBM), the most malignant primary brain cancer. Phenotypic profiling of the neurogenic small molecule KHS101 revealed the chemical induction of lethal cellular degradation in molecularly-diverse GBM cells, independent of their tumor subtype, whereas non-cancerous brain cells remained viable. Mechanism-of-action (MOA) studies showed that KHS101 specifically bound and inhibited the mitochondrial chaperone HSPD1. In GBM but not non-cancerous brain cells, KHS101 elicited the aggregation of an enzymatic network that regulates energy metabolism. Compromised glycolysis and oxidative phosphorylation (OXPHOS) resulted in the metabolic energy depletion in KHS101-treated GBM cells. Consistently, KHS101 induced key mitochondrial unfolded protein response factor DDIT3 in vitro and in vivo, and significantly reduced intracranial GBM xenograft tumor growth upon systemic administration, without discernible side effects. These findings suggest targeting of HSPD1-dependent oncometabolic pathways as an anti-GBM therapy.

cancer biology↗