TY - JOUR
T1 - Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models
AU - Portera-Cailliau, Carlos
AU - Hedreen, John C.
AU - Price, Donald L.
AU - Koliatsos, Vassilis E.
PY - 1995/5
Y1 - 1995/5
N2 - Huntington disease (HD) is an inherited neurodegenerative disorder characterized by selective death of striatal medium spiny neurons. Intrastriatal injections of glutamate receptor agonists (excitotoxins) recapitulate some neuropathological features of this disorder. Although this model suggests that excitotoxic injury may be involved in HD, the exact mechanisms of cell death in HD and its models are unknown. The present study was designed to test the hypothesis that HD can develop via the activation of an apoptotic mechanism of cell death and to examine whether excitotoxic striatal lesions with quinolinic acid in rats represent accurate models of HD. To characterize cell death, we employed DNA electrophoresis, electron microscopy (EM), and the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method for the in situ detection of DNA strand breaks. In the neostriatum of individuals with HD, patterns of distribution of TUNEL-positive neurons and gila were reminiscent of those seen in apoptotic cell death during normal development of the nervous system; in the same areas, nonrandom DNA fragmentation was detected occasionally. Following excitotoxic injury of the rat striatum, internucleosomal DNA fragmentation (evidence of apoptosis) was seen at early time intervals and random DNA fragmentation (evidence of necrosis) at later time points. In addition, EM detected necrotic profiles of medium spiny neurons in the lesioned rats. In concert, these results suggest that apoptosis occurs in both HD and excitotoxic animal models and that apoptotic and necrotic mechanisms of neuronal death may occur simultaneously within individual dying cells in the excitotoxically injured brain. However, the distribution of dying neurons in the neostriatum, the degree of glial degeneration, and the involvement of striatofugal pathways are very different between HD and excitotoxically damaged striatum. The present study suggests that multiple methods should be employed for a proper characterization of neuronal cell death in vivo.
AB - Huntington disease (HD) is an inherited neurodegenerative disorder characterized by selective death of striatal medium spiny neurons. Intrastriatal injections of glutamate receptor agonists (excitotoxins) recapitulate some neuropathological features of this disorder. Although this model suggests that excitotoxic injury may be involved in HD, the exact mechanisms of cell death in HD and its models are unknown. The present study was designed to test the hypothesis that HD can develop via the activation of an apoptotic mechanism of cell death and to examine whether excitotoxic striatal lesions with quinolinic acid in rats represent accurate models of HD. To characterize cell death, we employed DNA electrophoresis, electron microscopy (EM), and the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method for the in situ detection of DNA strand breaks. In the neostriatum of individuals with HD, patterns of distribution of TUNEL-positive neurons and gila were reminiscent of those seen in apoptotic cell death during normal development of the nervous system; in the same areas, nonrandom DNA fragmentation was detected occasionally. Following excitotoxic injury of the rat striatum, internucleosomal DNA fragmentation (evidence of apoptosis) was seen at early time intervals and random DNA fragmentation (evidence of necrosis) at later time points. In addition, EM detected necrotic profiles of medium spiny neurons in the lesioned rats. In concert, these results suggest that apoptosis occurs in both HD and excitotoxic animal models and that apoptotic and necrotic mechanisms of neuronal death may occur simultaneously within individual dying cells in the excitotoxically injured brain. However, the distribution of dying neurons in the neostriatum, the degree of glial degeneration, and the involvement of striatofugal pathways are very different between HD and excitotoxically damaged striatum. The present study suggests that multiple methods should be employed for a proper characterization of neuronal cell death in vivo.
KW - Huntington disease
KW - endonuclease
KW - excitotoxicity
KW - necrosis
KW - neostriatum
KW - programmed cell death
UR - http://www.scopus.com/inward/record.url?scp=0029072690&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029072690&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.15-05-03775.1995
DO - 10.1523/jneurosci.15-05-03775.1995
M3 - Article
C2 - 7751945
AN - SCOPUS:0029072690
SN - 0270-6474
VL - 15
SP - 3775
EP - 3787
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 5 II
ER -