Brain pathology of spinocerebellar ataxias

Abstract

The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein quality control, detailed molecular and pathogenetic consequences remain to be determined.

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

“…To determine the presence and localization of CSE, we performed immunohistochemistry for CSE on postmortem pontine tissue of control individuals and SCA3 patients. From the sparse tissue available for this rare disease, pontine tissue was chosen to analyze the features of this disorder, because in this tissue several types of toxic protein aggregates are present with enough neurons preserved to allow immunohistochemical analysis (7) in contrast to other brain areas that are almost completely degenerated or that hardly show degeneration or protein aggregation (51,52). As control samples, postmortem tissue of individuals without a neurodegenerative or neuropsychiatric disease were used (Supplementary Table S1; n = 7).…”

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

“…Not surprisingly, mutant ataxin-7 induced transcriptional dysregulation in SCA7 transgenic models [187][188][189], and the disease associates with nuclear aggregates of the polyQ-expanded protein [190]. 20 !…”

“…Studies with SCA17 transgenic mice indicate that polyQ expansion in TBP alters its ability to bind DNA and transcriptional regulators, suggesting that transcriptional dysregulation contributes to SCA17 pathogenesis [193][194][195][196]. In SCA17, mutant TBP accumulates in intranuclear aggregates [190].…”

“…Both patients and DRPLA animal models show nuclear accumulation of an N-terminal fragment of mutant atrophin-1, which forms aggregates and is associated with toxicity [190,199].…”

Tissue plasminogen activator regulates Purkinje neuron development and survival

“…Many fundamental concepts of modern neuroscience have been established by study of PNs (3), because their cell bodies and dendrites are readily and vividly accessible in vivo and in vitro (4). PNs are more susceptible than most neurons to degeneration in a variety of disorders, including several of the more than 30 known spinocerebellar ataxias (5), as well as some cases of fetal and adult chronic alcohol syndromes, paraneoplastic diseases, lysosomal storage diseases, autism spectrum disorders, and Alzheimer's disease (6)(7)(8). Although the causal gene in many of the heritable ataxias now has been identified, the basis for the PN defects remains almost entirely undefined (6).…”