Synapses in the hereditary ataxias

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.