According to new research, neurodegeneration in brain cells may occur when the natural cellular cleaning mechanism malfunctions due to low levels of a niacin-related coenzyme, depriving cells of energy.
Brain cells die due to autophagy failure, a process by which cells eliminate cellular waste and create energy for survival. Researchers discovered that a metabolic failure caused by autophagy loss is harmful to brain cells known as neurons in new research published in Cell Reports.
When autophagy fails, the levels of a coenzyme called nicotinamide adenine dinucleotide (NAD) decline, preventing cells from obtaining enough energy to operate normally and survive.
Researchers led by Dr. Sovan Sarkar at the University of Birmingham along with his Ph.D. students, Congxin Sun and Dr. Elena Seranova, and in collaboration with Prof. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research, developed a human embryonic stem cell (hESC) model with deletion of a key gene involved in autophagy.
They created neurons from these hESCs to learn more about how autophagy deficiency destroys brain cells. In autophagy-deficient neurons, depletion of NAD was identified to mediate cell death. The researchers discovered that when autophagy was lost, NAD was used by hyperactivation of naturally occurring enzymes such Sirtuins and PARPs.
Dropping NAD levels led in unwanted electrical alterations to mitochondria, causing them to be unable to operate properly and cells to be unable to digest energy to maintain homeostasis.
Both autophagy and NAD levels decline in our cells and tissues as we get older contributing to age-related diseases. Our study helps to explain how these processes are interlinked: loss of autophagy also causes depletion of NAD.
Dr. Viktor Korolchuk
The discoveries of this neurotoxic pathway, according to the researchers, present new hints regarding a technique to battle neurodegenerative illnesses by demonstrating that drugs that increase NAD levels can improve the survival of neurons with autophagy loss.
Dr. Sovan Sarkar, a Birmingham Fellow in the Institute of Cancer and Genomic Sciences at the University of Birmingham and lead senior author of the paper said, “We have shown a new mechanism of how brain cells are dying when autophagy stops working properly by using a hESC-derived neuronal model of autophagy deficiency. Autophagy is a critical process across all cells, especially in neurons, and identifying that NAD levels are being depleted when autophagy malfunctions is a very important step in thinking about a way to manage decline in brain health both in older age and among at-risk populations.”
“NAD can be boosted through the use of targeted therapeutics such as supplementation with NAD precursors like nicotinamide (NAM), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), as well as through the consumption of vitamin B3 also called niacin.”
“Our research also identifies the potential for drugs that slow down the NAD-eating enzymes in the PARP and Sirtuin families, all of which could support healthy aging and reduced risk of neurodegeneration.”
The findings imply that, among the various roles that autophagy plays, maintaining NAD levels that enable cell metabolism is a crucial component in preventing dementia.
It also provides new potential targets for future treatments for neurodegenerative diseases, both by targeting the enzymes (SIRT1 and 2 and PARP1 and 2) that ate up NAD and by supplementing NAD precursors.
Dr. Viktor Korolchuk, Associate Professor at Newcastle University and a senior co-author of the paper said, “Both autophagy and NAD levels decline in our cells and tissues as we get older contributing to age-related diseases. Our study helps to explain how these processes are interlinked: loss of autophagy also causes depletion of NAD.”
“Our recent paper demonstrated this in yeast and mouse cells, and the current study in human cells unequivocally shows that this intimate link between autophagy and NAD can trigger the death of human neurons. This finding significantly adds to our understanding of aging and age-related neurodegeneration and opens new avenues to explore.”
