Physiology in MedicineApoptosis and neurologic disease☆
Section snippets
The setting for apoptosis
Normal embryonic and postnatal development includes cell death, which is generally of the apoptotic variety. As the result of either endogenous signals or intercellular signaling processes, activation of programs of cell death occurs in certain cells. These cells are developmentally superfluous either due to having already served their scaffolding or temporary function or due to cellular overproduction, faulty migration, or “erroneous” connectivity. Selective cell death is thus a standard
Cellular events in apoptosis
Cytoplasmic processes that are abnormally active in apoptosis include, most importantly, a variety of proteolytic enzymes, members of the caspase family, which are usually activated as part of a proteolytic cascade in apoptosis. The actions of these enzymes destroy important cellular machinery, preventing the synthesis of new proteins and ultimately leading to irreversible injury Figure 2, Figure 3. The caspase family, as presently described, consists of 10 proteolytic enzymes, named as such
Factors that may cause or induce apoptosis
Growth factor deficiencies prompt apoptosis in the developing nervous system. Thus it is natural to suspect that loss of retrogradely transported neurotrophic factors might be important in causing programmed cell death in adult neurons. Oxidative stress is a presumptive cause of apoptosis. In particular the relationship of mitochondrial failure to apoptosis is strong. A known signal for apoptosis is change in mitochondrial permeability, leading to release of cytochrome c into the cytoplasmic
Amyotrophic lateral sclerosis
Loss of motor neurons is a hallmark of amyotrophic lateral sclerosis, a relatively rapidly progressive disease in which spinal motor neurons and upper motor neuron pathways degenerate, leading ultimately to complete paralysis of all general somatic musculature. Death usually occurs within 3 years from respiratory insufficiency or its complications. ALS is also known as motor neuron disease in Great Britain. In the United States, it is often referred to as Lou Gehrig’s disease, after the famous
Summary
Apoptotic cell death likely occurs in a spectrum of neurologic disorders. In many chronic neurodegenerative diseases, it is likely that cell death does play a primary role in loss of function, although this is not proven. For example, it remains a strong possibility that synaptic injury precedes neuronal injury in Alzheimer’s disease. Assuming a primary, or even secondary, role for cell death in degenerating nervous system diseases, there is suggestive evidence for a variety of conditions,
Acknowledgements
We wish to thank Dr. Fred Baskin for reviewing the manuscript, and Dr. Jeffrey L. Elliott for manuscript comments and many valuable discussions.
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Supported by an Alzheimer’s Disease Center NIH Grant, 5P30-AG12300 (RNR, LSH), NIH Grant 5R01-DK45923 (LSH), and UT President’s Research Council Award (LSH).