(515.15) Infantile Neurodegeneration results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 rather than Aβ-Binding Alcohol Dehydrogenase

Poster Board Number: A402

song-yu yang (NYS Institute for Basic Research), Xue-Ying He (NYS Institute for Basic Research), Carl Dobkin (NYS Institute for Basic Research), W. Ted Brown (University of Sydney)

Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10), a mitochondrial homo-tetrameric multifunctional protein encoded by the HSD17B10 gene is necessary for brain cognitive function. Missense mutations on this gene resulted in HSD10 mitochondrial disease, an inborn error in isoleucine metabolism. A 5-methylcytosine hotspot in this gene underlying a 388C ̵T transition leads to the HSD10(p.R130C) mutant responsible for about half cases of infantile neurodegeneration. Less females suffers with this disease and usually has milder clinical manifestation due to the X-inactivation. The binding capability of this dehydrogenase to Aβ-peptide may play a role in senile neurodegeneration, namely Alzheimer disease, but it appears unrelated to infantile neurodegeneration. Unfortunately, this research field has been interfered by reports of the Aβ-peptide binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ binding protein (ERAB). Both reflect some dubious features of 17β-HSD10. It is clarified here that ERAB is merely a subunit of 17β-HSD10, having a fictitious association with the endoplasmic reticulum. 17β-HSD10 exhibits L-3-hydroxyacyl-CoA dehydrogenase activity so also known as short chain 3-hydorxyacyl-CoA dehydrogenase (SCHAD), but it is not involved in the ketone body metabolism as reported for ABAD’s function in the cellular response to nutritional stress. Furthermore, the reported generalized alcohol dehydrogenase data underlying the ABAD activity could not be based upon valid reproducible experiments, and the rediscovery of its mitochondrial localization was preceded by unreferenced 17β-HSD10 research. Clarification of unreliable ABAD/ERAB data may invigorate this research field, and open new approaches to the understanding and treatment of the HSD17B10 gene related disorders including infantile neurodegeneration and Alzheimer’s disease.

Supported in part by the New York State Office for People With Developmental Disabilities