Series Introduction: Neurodegeneration: What is it and where are we?

“Neurodegeneration” is a commonly used word whose meaning is believed to be universally understood. Yet finding a precise definition for neurodegeneration is much more arduous than one might imagine. Often, neurodegeneration is only casually mentioned and scarcely discussed in major medical textbooks and is even incompletely defined in the most comprehensive dictionaries. Etymologically, the word is composed of the prefix “neuro-,” which designates nerve cells (i.e., neurons), and “degeneration,” which refers to, in the case of tissues or organs, a process of losing structure or function. Thus, in the strict sense of the word, neurodegeneration corresponds to any pathological condition primarily affecting neurons. In practice, neurodegenerative diseases represent a large group of neurological disorders with heterogeneous clinical and pathological expressions affecting specific subsets of neurons in specific functional anatomic systems; they arise for unknown reasons and progress in a relentless manner. Conversely, neoplasm, edema, hemorrhage, and trauma of the nervous system, which are not primary neuronal diseases, are not considered to be neurodegenerative disorders. Diseases of the nervous system that implicate not neurons per se but rather their attributes, such as the myelin sheath as seen in multiple sclerosis, are not neurodegenerative disorders either, nor are pathologies in which neurons die as the result of a known cause such as hypoxia, poison, metabolic defects, or infections. Among the hundreds of different neurodegenerative disorders, so far the lion’s share of attention has been given only to a handful, including Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS). Many of the less common or publicized neurodegenerative disorders, though no less devastating, have remained essentially ignored. The most consistent risk factor for developing a neurodegenerative disorder, especially AD or PD, is increasing age (1). Over the past century, the growth rate of the population aged 65 and beyond in industrialized countries has far exceeded that of the population as a whole. Thus, it can be anticipated that, over the next generations, the proportion of elderly citizens will double, and, with this, possibly the proportion of persons suffering from some kind of neurodegenerative disorder. This prediction is at the center of growing concerns in the medical community and among lawmakers, for one can easily foresee the increasing magnitude of emotional, physical, and financial burdens on patients, caregivers, and society that are related to these disabling illnesses. Compounding the problem is the fact that while, to date, several approved drugs do, to some extent, alleviate symptoms of several neurodegenerative diseases, their chronic use is often associated with debilitating side effects, and none seems to stop the progression of the degenerative process. In keeping with this, the development of effective preventive or protective therapies has been impeded by the limitations of our knowledge of the causes and the mechanisms by which neurons die in neurodegenerative diseases. Despite this bleak outlook, several neurobiological breakthroughs have brought closer than ever the day when the secrets of several neurodegenerative disorders will be unlocked and effective therapeutic strategies will become available. In this Perspective series, selected genetic and molecular advances relevant to the biology of neurodegeneration — e.g., to apoptosis, oxidative stress, and mitochondrial dysfunction — will be reviewed. While some of these will be discussed in terms of generic mechanisms underlying neuronal death, others will be discussed in the context of a specific disease such as ALS or HD. From the various Perspectives in this series, readers may obtain a comprehensive update on prominent neurodegenerative conditions from both a clinical and a molecular viewpoint. As a preamble to the series, however, it would be useful to discuss some general notions related to neurodegeneration that should help set the stage for the more detailed articles to follow.