Abstract
Introduction Since the mid-1990s, the specific etiologies and mechanisms leading to dysfunction and loss of motor neurons in ALS have been under intensive investigation. No single mechanism appears to explain the devastating and inexorable injury to motor neurons. What appears far more likely is a convergence of a number of different mechanisms that collectively or sequentially impair motor neuron structure and function. Among the various proposals implicated, increased free radicals and oxidative stress, increased glutamate excitotoxicity, increased cellular aggregates and increased intracellular calcium have received the most attention (Rothstein, 1995; Cleveland, 1999; Shaw & Eggett, 2000; Rowland, 2000; Julien, 2001; Rowland & Shneider, 2001; Cleveland & Rothstein, 2001). None of these mechanisms is mutually exclusive and altered calcium homeostasis, free radicals, and glutamate excitotoxicity may all participate in the cell injury cascade leading to motor neuron death. Alterations in one parameter can lead to alterations in other parameters, and each can enhance and propagate the injury cascade. Such perturbations could critically impair motor neuron mitochondria and neurofilaments, compromise energy production and axoplasmic flow, and impair synaptic function. However, these alterations would be expected to adversely affect most neurons, and the critical question is why motor neurons are uniquely sensitive to injury in ALS, and why some motor neurons are relatively resistant to injury. Our own hypothesis focuses on the critical role of intracellular calcium and the inability of vulnerable motor neurons to handle an increased intracellular calcium load, possibly related to the relative paucity of the calcium binding proteins, calbindin D28k and parvalbumin.
Original language | English (US) |
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Title of host publication | Neurodegenerative Diseases |
Subtitle of host publication | Neurobiology, Pathogenesis and Therapeutics |
Publisher | Cambridge University Press |
Pages | 65-79 |
Number of pages | 15 |
ISBN (Electronic) | 9780511544873 |
ISBN (Print) | 052181166X, 9780521811668 |
DOIs | |
State | Published - Jan 1 2005 |
ASJC Scopus subject areas
- Medicine(all)