Chromatolysis

In 1885, researcher Walther Flemming described dying cells in degenerating mammalian ovarian follicles. The cells showed variable stages of pyknotic chromatin. These stages included chromatin condensation, which Flemming described as "half-moon" shaped and appearing as "chromatin balls," or structures resembling large, smooth, and round electron-dense chromatin masses. Other stages included cell fractionation into smaller bodies. Flemming named this degenerative process "chromatolysis" to describe the gradual disintegration of nuclear components. The process he described now fits with the relatively new term, apoptosis, to describe cell death. Around the same time of Flemming's research, chromatolysis was also studied in the lactating mammary glands and in breast cancer cells. From observing the regression of ovarian follicles in mammals, it was argued that a necessary cellular process existed to counterbalance the proliferation of cells by mitosis. At this time, chromatolysis was proposed to play a major role in this physiological process. Chromatolysis was also thought to be responsible for necessary cell elimination in various organs during development. Again, these expanded definitions of chromatolysis are consistent with what we now term apoptosis. In 1952, research further supported the role of chromatolysis in changing the physiology of cells during cell death processes in embryo development. It was also observed that the integrity of mitochondria is maintained during chromatolysis. By the 1970s, the conserved structural features of chromatolysis were identified. The consistent features of chromatolysis included the condensation of the cytoplasm and chromatin, cell shrinkage, formation of "chromatin balls," intact normal organelles, and fragmentation of cells observed by the budding of fragments enclosed in the cell membrane. These budding fragments were termed "apoptotic bodies," thus coining the name "apoptosis" to describe this form of cell death. The authors of these studies, most likely unfamiliar with older publications on chromatolysis, were essentially describing apoptosis as a process identical to chromatolysis. ==Types of chromatolysis==

Central chromatolysis Central chromatolysis is the most common form of chromatolysis and is characterized by the loss or dispersion of the Nissl bodies starting near the nucleus at the center of the neuron, and then extending peripherally towards the plasma membrane. Also characteristic of central chromatolysis is the displacement of the nucleus towards the periphery of the perikaryon. Other cellular changes are observed during the process of the central chromatolysis. The process of Nissl dissolution is less apparent toward periphery of the cell body of the neuron, where normal-looking Nissl bodies may be present. Peripheral chromatolysis Peripheral chromatolysis is much less common, but has been reported to occur after axotomy and ischemia in certain species. Peripheral chromatolysis is essentially the reverse of central chromatolysis, in which the disintegration of Nissl bodies is initiated at the periphery of the neuron and extends inwards towards the nucleus of the cell. Peripheral chromatolysis has been observed to occur in lithium-induced chromatolysis and it could be useful in investigating and countering the hypothesis that waves of enzymatic activity always progress from the perinuclear area, or the area situated around the nucleus, to the peripheral of the cell. ==Causes==

with Nissl bodies and lipofuscin. The pink structures are Nissl bodies and the blue and yellow structures are the lipofuscin granules. In chromatolysis of motor neurons, these pink structures dissolve. Axotomy When an axon is injured, the whole neuron reacts to provide increased metabolic activity that is necessary for regeneration of the axon. Part of this reaction includes structural alternations caused by the chromatolysis event. The enlargement of nuclear components due to axotomy can be explained by the alteration of the cell's cytoskeleton. The cytoskeleton maintains the nuclear components of a cell and the size of the cell body in neurons. The increase in protein within the neuron leads to this change in the cytoskeleton. For example, there is an increase in phosphorylated neurofilament proteins and cytoskeletal components, tubulin and actin, in neurons undergoing chromatolysis. Lithium Exposure to lithium has also been used as a method to induce chromatolysis in rats. The study involved the injection of large doses of lithium chloride into female Lewis rats over several day periods. Examination of the trigeminal and dorsal root ganglia revealed peripheral chromatolysis in these cells. The cells exhibited decreased numbers of Nissl bodies throughout the cell, especially at the peripheral cytoplasm were the Nissl bodies were completely absent. Using lithium as a method to induce peripheral chromatolysis could be useful for future study of chromatolysis due to its simplicity and the fact it does not cause nuclear displacement. ==Associated diseases==

Amyotrophic lateral sclerosis (ALS) Central chromatolysis has been observed in spinal anterior horn and motor neurons of patients with amyotrophic lateral sclerosis (ALS). Patients with ALS appear to have significant alterations that occur within the chromatolyzed neuronal cells. These alterations include dense conglomerates of aggregated dark mitochondria and presynaptic vesicles, bundles of neurofilaments, and a marked increase of presynaptic vesicles. Changes to the function of the motor neurons have also been observed. The most typical functional change in chromatolytic motor neurons is the significant reduction in size of the monosynaptic excitatory postsynaptic potentials (EPSPs). These monosynaptic EPSPs also seem to be prolonged in the chromatolyzed cells of ALS patients. This functional change to the anterior horn neurons could result in the elimination of certain excitatory synaptic inputs and thus give rise to the clinical motor function impairment that is characteristic of the ALS disease. Most recent studies have observed chromatolysis in cells from rats that have been subjected to either copper or aluminum toxication, which are both hypothesized to be involved in the pathogenesis of Alzheimer's disease. Idiopathic brainstem neuronal chromatolysis Severe neuronal chromatolysis has been detected in the brainstems of adult cattle with the neurodegenerative condition known as idiopathic brainstem neuronal chromatolysis (IBNC). The symptoms of IBNC in cattle are clinically similar to those characterized by bovine spongiform encephalopathy, otherwise known as mad-cow disease. These symptoms included tremor, lack of muscle movement coordination, anxiety and weight loss. At the cellular level, IBNC is marked by the degeneration of neurons and axons within the brainstem and cranial nerves. The disease also has a significant correlation with abnormal labeling for prion protein (PrP) in the brain. IBNC has been characterized by severe neuronal, axonal, and myelin degradation, accompanied by non-supportive inflammation and changes in spongiform of various regions of grey matter. A significant loss of neurons due to hippocampal degeneration has also been observed. The degenerate chromatolysis neurons seldom showed intracytoplasmic labeling for PrP. Alcoholic encephalopathy Chromatolysis has been reported in patients with alcoholic encephalopathies. Central chromatolysis was observed mainly among neurons in the brainstem, particularly in the pontine nuclei and the cerebellar dentate nuclei. Nuclei of cranial nerves, arcuate nuclei, and posterior horn cells were also affected. Studies examining patients with alcoholic encephalopathies give evidence of central chromatolysis. Mild to severe degeneration of spinal cord tracks has been observed in patients with Marchiafava–Bignami disease and Wernicke–Korsakoff syndrome, both forms of encephalopathy linked to alcohol. ==Future research==

The mechanisms and signals for chromatolysis were first researched in depth in the 1960s and still merit further investigation. It is clear that axotomy is one of the most direct inducers of chromatolysis and if further research were put into elucidating the specific pathways which associate axonal damage to chromatolysis, then potential therapies could be developed for halting the chromatolytic response of neurons and ameliorating the detrimental effects of degenerative diseases, such as Alzheimer's and ALS. ==References==