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“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 neuron Perspective series.
As we have mentioned, HD has received at great deal of attention in the field of neuroscience, as it is a prototypic model of a genetic neurodegenerative disease. While it is well established that a triplet-repeat CAG expansion mutation in the huntingtin gene on chromosome 4 is responsible for HD, Anne B. Young (39) will bring us on the chaotic trail of research that aims to define the normal functioning of this newly identified protein, as well as to elucidate the intimate mechanism by which the mutant huntingtin kills neurons. Although much remains to be done, this article provides us with an update on the most salient advances made in the past decade in the field of HD, suggests pathological scenarios as to how mutant huntingtin may lead to HD, and, most importantly, discusses the many steps in the process of functional decline and cell death that might be targeted by new neuroprotective therapies (39).
While HD is by nature a genetic condition, PD is only in rare instances an inherited disease. Despite this scarcity, many experts in the field of neurodegeneration share the belief that these rare genetic forms of PD represent unique tools to unravel the molecular mechanisms of neurodegeneration in the sporadic form of PD, which accounts for more than 90% of all cases. Accordingly, Ted Dawson and Valina Dawson review, in their Perspective, the different genetic forms of PD identified to date (40). They then summarize the current knowledge on the normal biology of two proteins, a-synuclein and parkin, whose mutations have been linked to familial PD (40). The authors also discuss how these different proteins may interact with each other and how, in response to the known PD-causing mutations, they may trigger the neurodegenerative processes (40).
The recognition that many neurodegenerative diseases are associated with some sort of intra- or extracellular proteinaceous aggregates has sparked major interest in the idea that these amorphous deposits may play a pathogenic role in the demise of specific subsets of neurons in various brain diseases. Along this line, what could be a better example of “proteinopathic” neurodegenerative disease than AD, which features NFTs and senile plaques? In this context, Todd Golde (41) reviews the presumed role of amyloid β protein (Aβ) in the initiation of AD and outlines the molecular scenario by which Aβ may activate the deleterious cascade of events ultimately responsible for dementia and cell death in AD. In light of this information the author discusses the different therapeutic approaches that may be envisioned for AD (41). He also summarizes the state of our knowledge about risk factors and biomarkers for AD that can be used to detect individuals at risk for developing the disease, and to follow its progression once it has developed (41).
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