Recent advances in preventing neurodegenerative diseases

Abstract

The worldwide health-care burden of neurodegenerative diseases is on the rise-a crisis created through a combination of increased caseload and lack of effective treatments. The limitations of pharmacotherapy in these disorders have led to an urgent shift toward research and clinical trials for the development of novel compounds, interventions, and methods that target shared features across the spectrum of neurodegenerative diseases. Research targets include neuronal cell death, mitochondrial dysfunction, protein aggregation, and neuroinflammation. In the past few years, there has been a growth in understanding of the pathophysiologic mechanisms of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. This increase in knowledge has led to the discovery of numerous novel neuroprotective therapeutic targets. In this context, we reviewed and summarized recent advancements in neuroprotective strategies in neurodegenerative diseases.

Figure 1.. Cell-autonomous and non-cell-autonomous neurodegeneration.

PARP1-dependent cell-autonomous mechanisms of neurodegeneration (bottom). Neuron injury stressors such as an oxidative stress or aggregated proteins activate nitric oxide synthase that produces nitric oxide and then peroxynitrite (ONOO⁻), resulting in overactivation of PARP1. Accumulated poly (ADP-ribose) (PAR) polymers synthesized by overactivated PARP1 translocate from the nucleus to the cytoplasm and mitochondria, where it binds to and induces mitochondrial release of apoptosis-inducing factor (AIF). AIF-bound macrophage migration-inducing factor (MIF) nuclease translocates into the nucleus, where MIF cleaves genomic DNA into large-scale fragments, causing cell death. Inhibition of PARP1 can protect neurons in a variety of neurodegenerative diseases (see ‘Prevention of cell-autonomous neurodegeneration’ section). Non-cell-autonomous mechanisms of neurodegeneration mediated by microglia or astrocytes (top). Induction of disease-associated microglia or homeostatic microglia and subsequent prevention of neurotoxic microglia could be promising neuroprotection strategies in neurodegenerative diseases. Alternatively, activated microglia induces the formation of neurotoxic reactive astrocytes by secreting interleukin 1α (IL-1α), tumor necrosis factor α (TNF-α), and C1q. Reactive astrocyte-targeted neuroprotection could be achieved by microglial inhibition of formation of neurotoxic reactive astrocytes and induction of neuroprotective astrocytes. PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species.