Targeting the autophagy-NAD axis in rare early-onset neurodegenerative diseases
Lead Research Organisation:
University of Birmingham
Department Name: Institute of Cancer and Genomic Sciences
Abstract
Nervous system disorders include common diseases like dementia, and rare genetic disorders, often childhood-onset. In the UK, they affect >944,000 people, forecasted to increase to >1 million by 2025. However, for about 150 rare brain disorders, therapeutic discovery is hampered by their rarity and low commercial incentive. Limited knowledge of disease mechanisms by which the brain cells called neurons die, a process termed neurodegeneration, has also undermined drug discovery.
The focus of this proposal is to understand and target common disease mechanisms that underpin several childhood-onset forms of neurodegeneration. Targeting shared pathological mechanisms will allow us to use the same treatment for other rare disorders. One such common mechanism affected in several neurological disorders is a biological process called autophagy. This process has a housekeeping role in cells by removing undesirable cellular components such as protein aggregates and damaged organelles like mitochondria. When autophagy malfunctions, unwanted cellular components build up and the cell may eventually die, with neurons being particularly vulnerable. We recently demonstrated a new paradigm of the pro-survival role of autophagy via maintenance of cellular levels of a metabolite called nicotinamide adenine dinucleotide (NAD). Loss of autophagy disrupted mitochondrial quality control, triggering over-activation of stress responses mediated by enzymes that consume NAD. Depletion of NAD perturbed the mitochondrial electrical potential that led to cell death. Supplementation with NAD precursors restored NAD levels, mitochondrial bioenergetics, and protein homeostasis, thereby preventing neuronal death caused by autophagy deficiency.
Our goal is to target this mechanism of cell death in rare, early-onset neurodegenerative diseases associated with defective autophagy for developing treatments. We will focus on Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS), and assess generalisability in Lafora disease and neuronal ceroid lipofuscinosis 3 (CLN3 disease). These diseases have no effective cure and are associated with a spectrum of autophagy defects at early/late stages that we and others have demonstrated. We also found lower NAD levels in NPC1 and WS patient-derived neurons where drugs increasing autophagy or NAD improved neuronal survival.
Our work will deliver insights into common patho-mechanisms and potential treatments for a range of rare neurodegenerative diseases associated with autophagy defects. First, we will study the contribution of autophagy dysfunction to cell death in rare disease models by analysing the intermediate steps of the cytotoxic pathway involving mitochondrial abnormalities and NAD metabolism. Then, we will use drugs that can correct the autophagy and NAD deficits, and further evaluate their efficacy in rescuing various disease-relevant phenotypes. Finally, we will investigate whether the treatment strategy will work for other rare brain disorders.
To test new therapy in clinically relevant cells, we will make neurons from stem cells generated from patients' skin samples. We will use them to study how neurons die from autophagy malfunction that will lead to establishing a common disease mechanism involving autophagy dysfunction and NAD depletion. We will then test medicines already in use for other conditions or used as nutritional supplements to rescue the autophagy and NAD defects for improving the survival of patient-derived neurons, and applicable to multiple rare disease conditions. Our treatment strategy will be put forward in a future proposal for a clinical trial in children with rare brain disorders. The outcome will improve the health of children and have wider societal benefits to the rare disease community, neurologists, basic scientists, and NHS.
The focus of this proposal is to understand and target common disease mechanisms that underpin several childhood-onset forms of neurodegeneration. Targeting shared pathological mechanisms will allow us to use the same treatment for other rare disorders. One such common mechanism affected in several neurological disorders is a biological process called autophagy. This process has a housekeeping role in cells by removing undesirable cellular components such as protein aggregates and damaged organelles like mitochondria. When autophagy malfunctions, unwanted cellular components build up and the cell may eventually die, with neurons being particularly vulnerable. We recently demonstrated a new paradigm of the pro-survival role of autophagy via maintenance of cellular levels of a metabolite called nicotinamide adenine dinucleotide (NAD). Loss of autophagy disrupted mitochondrial quality control, triggering over-activation of stress responses mediated by enzymes that consume NAD. Depletion of NAD perturbed the mitochondrial electrical potential that led to cell death. Supplementation with NAD precursors restored NAD levels, mitochondrial bioenergetics, and protein homeostasis, thereby preventing neuronal death caused by autophagy deficiency.
Our goal is to target this mechanism of cell death in rare, early-onset neurodegenerative diseases associated with defective autophagy for developing treatments. We will focus on Niemann-Pick type C1 (NPC1) disease and Wolfram syndrome (WS), and assess generalisability in Lafora disease and neuronal ceroid lipofuscinosis 3 (CLN3 disease). These diseases have no effective cure and are associated with a spectrum of autophagy defects at early/late stages that we and others have demonstrated. We also found lower NAD levels in NPC1 and WS patient-derived neurons where drugs increasing autophagy or NAD improved neuronal survival.
Our work will deliver insights into common patho-mechanisms and potential treatments for a range of rare neurodegenerative diseases associated with autophagy defects. First, we will study the contribution of autophagy dysfunction to cell death in rare disease models by analysing the intermediate steps of the cytotoxic pathway involving mitochondrial abnormalities and NAD metabolism. Then, we will use drugs that can correct the autophagy and NAD deficits, and further evaluate their efficacy in rescuing various disease-relevant phenotypes. Finally, we will investigate whether the treatment strategy will work for other rare brain disorders.
To test new therapy in clinically relevant cells, we will make neurons from stem cells generated from patients' skin samples. We will use them to study how neurons die from autophagy malfunction that will lead to establishing a common disease mechanism involving autophagy dysfunction and NAD depletion. We will then test medicines already in use for other conditions or used as nutritional supplements to rescue the autophagy and NAD defects for improving the survival of patient-derived neurons, and applicable to multiple rare disease conditions. Our treatment strategy will be put forward in a future proposal for a clinical trial in children with rare brain disorders. The outcome will improve the health of children and have wider societal benefits to the rare disease community, neurologists, basic scientists, and NHS.
Technical Summary
Brain disorders include common diseases like dementia, and rare genetic disorders that are often childhood-onset. Finding a cure for ~150 rare diseases is challenging because of their rarity, low commercial incentive, and limited knowledge of the disease process such as how neurons die. The goal of our research is to improve the health of people with rare, childhood-onset forms of neurodegeneration. We aim to establish a common disease process that many of them share and to target that process so that the same treatment can also be used in other rare disorders.
In neurological disorders, a commonly affected process is autophagy, which has a housekeeping role in cells by removing undesirable cellular components including protein aggregates and damaged organelles like mitochondria. When autophagy malfunctions, unwanted cell components build up and the cell can eventually die. Neurons are particularly affected due to this. We recently showed that autophagy promotes cell survival by maintaining the cellular level of a metabolite called nicotinamide adenine dinucleotide (NAD), whereas loss of autophagy causes neuronal cell death via NAD depletion and the consequent mitochondrial dysfunction.
The objective of this proposal is to target the mechanism of cell death in rare, early-onset neurodegenerative diseases associated with defective autophagy. We will focus on Niemann-Pick type C1 disease and Wolfram syndrome, and then assess generalisability in Lafora disease and neuronal ceroid lipofuscinosis 3. We will utilize patient-derived induced pluripotent stem cells for differentiating them into neuronal cells to study the disease mechanisms pertaining to the defective autophagy-NAD axis. We will further develop therapeutics by using repurposed drugs and nutritional supplements to rescue the autophagy and NAD deficits. Our treatment strategy will be put forward in a future proposal for a clinical trial in children with rare brain disorders.
In neurological disorders, a commonly affected process is autophagy, which has a housekeeping role in cells by removing undesirable cellular components including protein aggregates and damaged organelles like mitochondria. When autophagy malfunctions, unwanted cell components build up and the cell can eventually die. Neurons are particularly affected due to this. We recently showed that autophagy promotes cell survival by maintaining the cellular level of a metabolite called nicotinamide adenine dinucleotide (NAD), whereas loss of autophagy causes neuronal cell death via NAD depletion and the consequent mitochondrial dysfunction.
The objective of this proposal is to target the mechanism of cell death in rare, early-onset neurodegenerative diseases associated with defective autophagy. We will focus on Niemann-Pick type C1 disease and Wolfram syndrome, and then assess generalisability in Lafora disease and neuronal ceroid lipofuscinosis 3. We will utilize patient-derived induced pluripotent stem cells for differentiating them into neuronal cells to study the disease mechanisms pertaining to the defective autophagy-NAD axis. We will further develop therapeutics by using repurposed drugs and nutritional supplements to rescue the autophagy and NAD deficits. Our treatment strategy will be put forward in a future proposal for a clinical trial in children with rare brain disorders.