Most of the degenerative diseases, as emphasized in the earlier general comments, are characterized by the selective involvement of anatomically and physiologically related systems of neurons. This feature is exemplified by amyotrophic lateral sclerosis (ALS), in which the pathologic process is virtually limited to motor neurons of the cerebral cortex, brainstem, and spinal cord, and by the progressive ataxias, in which only the Purkinje cells of the cerebellum are affected. Many other examples could be cited (e.g., Friedreich ataxia, Parkinson disease) in which discrete neuronal systems disintegrate, leaving others unscathed. Thus, these degenerative diseases had in the past been called system atrophies. The selective vulnerability of certain systems of neurons is not an exclusive property of the degenerative diseases; several different processes of known cause have similarly circumscribed effects on the nervous system. Contrariwise, in many degenerative diseases, the pathologic changes are somewhat less selective and eventually quite diffuse. Even then, there is an early tendency to involve special categories of neurons.
As one would expect of any pathologic process that is based on the slow wasting and loss of neurons, not only the cell bodies but also their dendrites, axons, and myelin sheaths disappear, unaccompanied by an intense tissue reaction or cellular response. The cerebrospinal fluid (CSF) shows little, if any, change, or at most a slight increase in protein content. Moreover, because these diseases invariably result in tissue loss, imaging examination shows either no change or only a volumetric reduction (atrophy) with a corresponding passive enlargement of the CSF compartments. These findings distinguish the neuronal atrophies from other large classes of progressive disease of the nervous system, namely, tumors, infections, and processes of inflammatory type.
At the cellular level, several processes characterize the death of individual cells. Among these mechanism is apoptosis, a term borrowed from embryology to specify the mechanisms that lead to neuronal degeneration. The original meaning of the term refers to a naturally occurring cell death during development that is driven by the expression of genes over a short period of time (i.e., “programmed” cell death), leaving no trace of a pathologic reaction. The process of neuronal degeneration is quite different in that it refers to a series of changes in mature neurons that occur over a protracted period of time, leading to cell death and often leaving a discrete glial scar, but not to regional tissue necrosis. In some models of degenerative disease, cell loss involves activation of specialized genes, although the time course and cellular morphology are not apoptotic in the original sense of the term. It is increasingly apparent that mechanisms other than programmed cell death will prove central to understanding the degenerative diseases, and that the clinical features of these conditions are manifest even before cellular destruction occurs. For example, interference with synaptic signaling and dysfunction of supporting glia cells are equally important to morphologic neuronal death.
It will become clear in the following discussion that the current theme in the study of degenerative diseases is that of aggregation within specific neurons of normal cellular proteins such as amyloid, tau, synuclein, ubiquitin, and huntingtin. In some cases, the protein is overproduced as a result of the simple fact of a triplication or overactivity of its corresponding gene. In other instances, enzymatic cleavage of a normal precursor protein yields a product with physical properties that lead to its aggregation (as happens with amyloid in Alzheimer disease) or, there may be failure of the normal mechanisms of protein removal, resulting in its excess accumulation. As mentioned above, this has resulted in the denomination of groups of diseases by the type of protein aggregate: tauopathy, synucleinopathy, etc. Even this is an uncertain or intermediate classification as it is not known in most cases if the protein is the cause or the result of cellular damage, and in any case, the fundamental mechanisms of cellular destruction are still being determined.