Structural and immunocytochemical features of olivopontocerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype

Abstract

Neuropathological investigations performed on autopsied brain and spinal cords from 11 patients showed that spinocerebellar ataxia type 1 (SCA-1) can be distinguished from autosomal dominant spinocerebellar ataxia linked to SCA-2 and -3 loci on chromosomes 12 and 14, spinopontine, and the multisystem atrophies. The major diagnostic criteria were: absence of significant pars compacta nigral and locus coeruleus lesions, severe degeneration of olivocerebellar and dentatorubral pathways, extensive loss of Purkinje cells with partial sparing of flocculonodular lobes, severe atrophy of specific cranial nerve nuclei, mostly the third and 12th, extensive loss of motor neurons in anterior horns and Clarke's columns, and lack of oligodendroglial or neuronal cytoplasmic cytoskeletal inclusions. None of the brains displayed any significant immunoreactivity for the amyloid precursor protein or beta-amyloid peptide throughout the cortex. In conclusion, the type and neuroanatomical distribution of structural lesions were similarly reproduced in all probands at the end stage of SCA-1, to the point that they appeared to constitute a unique phenotype.

Endocannabinoid-Hydrolysing Enzymes in the Post-Mortem Cerebellum of Humans Affected by Hereditary Autosomal Dominant Ataxias

“…shrunken cell body, strongly reduced dendritic tree and axonal swellings) [8]; (2) a marked reactive microgliosis that was particularly evident in the white matter of the folia and that surrounding the dentate nucleus, as well as in the granular layer, and that also extends to the perivascular microglia [8], and (3) a marked astrogliosis evident in the granular layer, in the white matter of the folia or surrounding the dentate nucleus and, particularly, in the cerebellar cortex (located, among others, in the Bergmann glia) [8]. This pattern was found in all SCA types included in our study and was similar to the data described by other authors [18,19,20]. These observations are also important for the present study, as it was conducted with samples from the same patients and control subjects, although in this case we have investigated the two major enzymes that degrade endocannabinoids, observing a profile of changes relatively similar to the changes noted in cannabinoid receptors [8].…”

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

“…17 It is also a region affected early in the pathogenesis of SCA1. 18,19 The posterior lobe (caudal) plays an important role in motor coordination. 20 In mice that received 8×10 8 vg, molecular layer widths were similar in width to wildtype mice in caudal lobules, with measurable thinning in rostral lobules.…”

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…ATAXIN1 is expressed in the CNS throughout life, localized mainly in the nucleus, both in its normal and mutated configuration, with some cytoplasmic localization in cerebellar Purkinje cells . Characteristic neuropathological findings in SCA1 are the loss of Purkinje cells in the cerebellum and neurons in the inferior olivary complex (Robitaille et al, 1995). As described for other polyglutamine diseases such as Huntingdon's disease (HD) Davies et al, 1997), the presence of neuronal intranuclear inclusions (NIs) in Purkinje cells in human patients and in a transgenic mouse model (Skinner et al, 1997) represents a pathological hallmark of SCA 1.…”