Y. Nagata et al., NEUROCHEMICAL CHANGES IN THE SPINAL-CORD IN DEGENERATIVE MOTOR-NEURONDISEASES, Molecular and chemical neuropathology, 33(3), 1998, pp. 237-247
Human amyotrophic lateral sclerosis (ALS), a typical motor neuron dise
ase, is characterized pathologically by selective degenerative loss of
motoneurons in the CNS. We have demonstrated significant reductions o
f neurotransmitter-related factors, such as acetylcholine-(ACh)-synthe
sizing enzyme activity and glutamate and aspartate contents in the ALS
, compared to the non-ALS spinal cord obtained at autopsy. We have als
o shown considerable reductions in activities of cytochrome-e oxidase
(CO), an enzyme contributing to aerobic energy production, and transgl
utaminase (TG), a Ca2+-dependent marker enzyme for tissue degeneration
, in the ALS spinal cord. We found marked increases in fragmented glia
l fibrillary acidic protein (GFAP), a filamentous protein specifically
associated with reactive astrocytes, in the ALS spinal cord relative
to non-ALS tissue. These biochemical results corresponded well to path
omor-phological neuronal degenerative loss and reactive proliferation
of astroglial components in the ALS spinal cord tissue. However, these
results only indicate the final pathological and biochemical outcomes
of ALS, and it is difficult to follow up cause and process in the ALS
spinal cord during progression of the disease. Therefore, we used an
animal model closely resembling human ALS, motor neuron degeneration (
Mnd) mutant mice, a subline of C57BL/6 that shows late-onset progressi
ve degeneration of lower motor neurons with paralytic gait beginning a
round 6.5 mo of age, to follow the biochemical and pathological altera
tions during postnatal development. We detected significant decreases
in CO activity during early development and in activity of superoxide
dismutase (SOD), an antioxidant enzyme, in later stages in Mnd mutant
spinal cord tissue. TG activity in the Mnd spinal cord showed gradual
increases during early development reaching a maximum at 5 mo, and the
n tending to decrease thereafter. Amounts of fragmented GFAPs increase
d continuously during postnatal development in Mnd spinal cord. These
biochemical changes were observed prior to the appearance of clinical
motor dysfunctions in the Mnd mutant mice. Such biochemical analyses u
sing appropriate animal models will be useful for inferring the origin
and progression of human ALS.