The metabolic etiology of niacin deficiency

点击翻译按钮获取中文摘要

Niacin (vitamin B3) is required to make nicotinamide adenine dinucleotide (NAD). NAD is then used in all of our energy producing and molecule building reactions as a way of moving electrons. Thus, it is not surprising that niacin deficiency causes health problems. In humans, niacin deficiency causes the disease pellagra, which has the unique symptoms of sun-sensitive dermatitis and schizophrenia-like dementia. Of interest, deficiencies of other nutrients that participate in electron moving reactions (riboflavin, iron) do not lead to dermatitis or dementia. This puzzle has been partially solved by the discovery of ADP-ribosylation reactions, which use NAD in a very different way. The sun-sensitivity suggests a role for niacin in DNA repair processes, and much of the work in my lab has focused on NAD as a substrate for poly(ADP-ribose) formation, which happens in response to DNA damage and is required for effective DNA repair. We have found that niacin deficient rats have low levels of NAD and poly ADP-ribose in bone marrow cells, and a sensitivity to developing leukemias. We propose that megadoses of niacin will enhance apoptosis in cancer cells, while at the same time improving genomic stability in normal bone marrow cells. The dementia of niacin deficiency resolves rapidly with niacin treatment, suggesting that NAD participates in neuronal signaling pathways. A likely mechanism involves the formation of cyclic ADP-ribose, which controls calcium levels in neurons. We have found that niacin deficient rats have decreases in brain NAD and cyclic ADP-ribose, and they have altered spatial learning and changes in various behavioral tests. Most forms of learning are linked to changes in synaptic signaling that increase synapse strength (long term potentiation, LTP) or activly decrease synaptic strength (long term depression, LTD). In future work, we will examine LTP and LTD in hippocampal slices, use startle reflex to examine behaviours more associated with human dementia, and examine brain sections for structural and connectivity changes. I will continue to work on these and related projects to promote a better understanding of how niacin functions in metabolism and the role of altered ADP-ribosylation reactions in the pathologies of deficiency.