A. Stieber et al., The neuronal Golgi apparatus is fragmented in transgenic mice expressing amutant human SOD1, but not in mice expressing the human NF-H gene, J NEUR SCI, 173(1), 2000, pp. 63-72
Fragmentation of the Golgi apparatus (GA) of motor neurons was first descri
bed in sporadic amyotrophic lateral sclerosis (ALS) and later confirmed in
transgenic mice expressing the G93A mutation of the gene encoding the enzym
e Cu,Zn superoxide dismutase (SOD1(G93A)) found in some cases of familial A
LS. In these transgenic mice, however, the fragmentation of the neuronal GA
was associated with cytoplasmic and mitochondrial vacuoles not seen in ALS
. The present new series of transgenic mice expressing 14-17 trans gene cop
ies of SOD1(G93A), compared to 25 copies in the mice we studied previously,
showed consistent fragmentation of the GA of spinal cord motor neurons, ax
onal swellings, Lewy-like body inclusions in neurons and glia, but none of
the cytoplasmic or mitochondrial vacuoles originally reported. Thus, this a
nimal model recapitulates the clinical and most neuropathological findings
of sporadic ALS. Neurofilaments (NF) accumulate in axons and, less often, i
n neuronal perikarya in most cases of sporadic ALS and they have been impli
cated in its pathogenesis. In order to investigate whether fragmentation of
the neuronal GA also occurs in association with accumulation of perikaryal
NFs, we studied the organelle in transgenic mice expressing the heavy subu
nit of human neurofilaments (NF-H) which developed a motor neuronopathy res
embling ALS. The neuronal GA of mice expressing NF-H, however, was intact d
espite massive accumulation of NFs in both perikarya and axons of motor neu
rons. In contrast, in transgenic mice expressing SOD1(G93A), the GA was fra
gmented despite the absence of accumulation of perikaryal NFs. These findin
gs suggest that, in transgenic mice with neuronopathies caused by the expre
ssion of mutant SOD1(G93A) or the human NF-H, the GA and the perikaryal NFs
are independently involved in the pathogenesis. The evidence suggests that
the GA plays a central role in the pathogenesis of the vast majority of sp
oradic ALS and in FALS with SOD1 mutations. (C) 2000 Elsevier Science BN. A
ll rights reserved.