ABSTRACT
Pathological axonal degeneration is one of the common features of neurode-generative diseases, which can occur independently from neuronal cell death. By interrupting the functional or structural connectivity of neurocircuits, such axonal pathology can directly contribute to the onset and progression of clinical symptoms in patients. Therefore, delay or prevention of axonal damage is indispensable for effectively treating neurodegenerative diseases. Notably, pathological axonal degeneration is often distinct from several known types of programmed cell death, for example, apoptosis, necroptosis, or pyroptosis. Instead, this destructive process is intrinsically linked to energy metabolism, particularly the co-enzyme nicotinamide adenine dinucleotide (NAD+), within damaged axons. This book chapter reviews the history of the research field and highlights the landmark works elucidating the molecular mechanisms of pathological axonal degeneration. Also, critical questions that still await future investigations are discussed.
As one of the unique structures of neurons, axons act as the bridge between neurons and their innervating targets. By transducing action potentials, axonal connections form the foundation for neural development and functions. As a result, the structural and functional integrity of axons is essential for various neurophysiological processes, for example, sense, motility, memory, and cognition. Conversely, damage or destruction of axons causes the abnormality or breakdown of corresponding neural circuits, leading to severe neuropathological defects such as numbness, pain, blindness, paralysis, ataxia, dementia, and even death.
Through decades of research, pathological loss of axons has been documented as a hallmark feature in almost all types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease), multiple sclerosis, Guillain–Barré syndrome, Charcot–Marie–Tooth disease, glaucoma, traumatic neural injuries, and other types of central or peripheral neuropathy (Coleman, 2005; Coleman and Hoke, 2020; DiAntonio, 2019; Neukomm and Freeman, 2014; Wang et al., 2012). Further, it has become increasingly recognized that pathological axonal degeneration contributes to the onset and progression of clinical symptoms by directly interfering with normal neural functions. Therefore, molecular mechanisms underlying pathological axonal degeneration are integral to neurodegeneration, and preserving axonal structures inflicted by neurodegenerative insults should be indispensable for effective strategies to prevent, delay, or revert disease symptoms.
Research in the past decades has achieved some of the most important and exciting breakthroughs in unraveling pathological axonal degeneration. Such advances have opened up a new dimension to our understanding of this unique axonal pathology and neurodegenerative diseases in general. This book chapter aims to review the updated knowledge of pathological axonal degeneration, highlighting entry points that may eventually lead to conquering those currently incurable human diseases.
