The goal of this investigation was the systematic assessment of synapses in
the hereditary ataxias by the immunocytochemical and immunofluorescent vis
ualization of SNAP-25. a protein of the presynaptic membrane. Sections were
prepared from the cerebellar cortex, dentate nucleus, basis pontis, inferi
or olivary nuclei, and the spinal cord in 57 cases of autosomal dominant an
d recessive ataxia. The neuropathological phenotype included 18 cases of ol
ivopontocerebellar atrophy (OPCA). 14 cases of familial cortical cerebellar
atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of F
riedreich's ataxia (FA). Among the autosomal dominant ataxias, spinocerebel
lar ataxia type 1 (SCA-1), SCA-2, MJD/SCA-3, and SCA-6 were represented. Ex
panded guanine-adenine-adenine trinucleotide repeats were confirmed in 7 pa
tients with FA. The abundance of SNAP-25 was estimated by comparing the flu
orescence of the regions of interest to that of the frontal cortex, which w
as considered unaffected by the disease process. Despite severe Purkinje ce
ll loss, abundant SNAP-25 reaction product remained in the molecular layer
of FCCA and OPCA. Among the cases of OPCA, those identified as SCA-2 showed
the most severe overall synaptic destruction in cerebellum and brain stem.
In SCA-I, which caused either OPCA or FCCA, significant synaptic loss was
restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and
inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dent
ate nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA,
preservation of SNAP-25 in the dentate nucleus was characteristic of long
survival. Severe cases with short survival revealed synaptic depletion of t
he dentate nucleus. At the level of the spinal cord, synaptic loss in the d
orsal nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clini
cal progression of the hereditary ataxias could not be attributed to synapt
ic loss in a single anatomic structure of cerebellum, brain stem, or spinal
cord. Nevertheless, synaptic loss in dentate and inferior olivary nuclei c
orrelated more precisely with the severity of the ataxia than the changes i
n the cerebellar colter.