Title:
CHALLENGES FOR CURRENTLY INCURABLE DISORDERS

AKIRA KAKIZUKA, M.D., PH.D.
Kyoto University, Graduate School of Biostudies

Abstract:
Despite recent advances in the development of new drugs, there remain many incurable disorders, in which the major pathology in the affected organs is early cell death, which occurs long before somatic death. Indeed, currently no drug is available to prevent such early cell death in vivo. We have been working to elucidate the molecular bases of polyglutamine diseases, as informative models for neurodegeneration. We have obtained several lines of evidence that implicate VCP, an AAA-type ATPase with ubiquitous expression, as a major player causing neurodegeneration. Indeed, single amino-acid substitutions in VCP are responsible for two different inherited neurodegenerative disorders (IBMPFD and ALS), and these mutations commonly produce VCPs with elevated ATPase activities. These results point to potential benefits of decreasing the ATPase activities of VCP. In this presentation, I show the development and evaluation of novel “VCP modulators”, which we refer to as KUSs (Kyoto University substances). KUSs showed significant and specific inhibition of the ATPase activity of VCP, but did not overtly inhibit any cellular VCP functions, and thus we termed the KUSs “VCP modulators” rather than “VCP inhibitors”. Indeed, KUS treatment (and exogenous ATP treatment as well) prevented the decrease of ATP levels, ER stress, and eventually cell death under conditions that lead to reductions in ATP pools, e.g. glucose or serum starvation, tunicamycin-induced ER stress, etc, in cultured cells. We then demonstrate in two different mouse models of incurable eye diseases, namely glaucoma and retinitis pigmentosa, that KUSs are efficacious in preventing retinal neuronal cell death in vivo. Namely, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. Likewise, in a mouse model of retinitis pigmentosa, the compounds prevented photoreceptor cell death and preserved visual function. These results reveal an unexpected, crucial role of VCP in determining cell fate in these pathological contexts, and point to a promising new cell-protective strategy for currently incurable diseases. I also present our recent finding that Hop flower extracts have good efficacies to prevent disease phenotypes of mouse models of Alzheimer disease via the inhibition of γ secretase activities.

References:
Ikeda H, Sasaoka N, Koike M, Nakano N, Muraoka Y, Toda Y, Fuchigami T, Shudo T, Iwata A, Hori S, Yoshimura N, & Kakizuka A. Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosa. Scientific Reports 4:5970, 2014.

Sasaoka N, Sakamoto M, Kanemori S, Kan M, Tsukano C, Takemoto Y, Kakizuka A. Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice. PLoS One.9:e87185, 2014.