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U. Rub, K. Burk, D. Timmann, W. den Dunnen, K. Seidel, K. Farrag, E. Brunt, H. Heinsen, R. Egensperger, A. Bornemann, S. Schwarzacher, H.-W. Korf, L. Schols, J. Bohl and T. Deller (2012) Neuropathology and Applied Neurobiology 38, 665680 Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights Aims: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. Methods: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. Results: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. Conclusions: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Contains fulltext : 81519.pdf (Publisher’s version ) (Closed access) AIMS: Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive. METHODS: We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients. RESULTS: This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients. CONCLUSIONS: In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.

BACKGROUND: The Bouvier des Flandres (BdF) dog is predisposed to develop prostate carcinoma (PCA). In humans, ethnic groups with higher prevalence of PCA have higher serum androgens concentrations and shorter polyglutamine (CAG) repeat lengths in the androgen receptor (AR) gene. In dogs, shorter CAG-I lengths are associated with increased PCA risk. OBJECTIVE: To compare serum androgens concentrations in the BdF with other breeds and to determine whether CAG repeats length and plasma androgens concentrations are correlated. MATERIALS AND METHODS: Androgens were measured in 46 BdF and in 53 other dog breed. Length of CAG-I and CAG-III repeats were measured in 41 BdF and correlated with androgen levels. RESULTS: In the BdF group shorter CAG-I and longer CAG-III repeat lengths were associated with lower androgen concentrations. CONCLUSION: As the shorter CAG-I repeat is associated with an increased PCA risk, higher androgen concentrations may protect against the development and progression of PCA.

BACKGROUND: The Bouvier des Flandres (BdF) dog is predisposed to develop prostate carcinoma (PCA). In humans, ethnic groups with higher prevalence of PCA have higher serum androgens concentrations and shorter polyglutamine (CAG) repeat lengths in the androgen receptor (AR) gene. In dogs, shorter CAG-I lengths are associated with increased PCA risk. OBJECTIVE: To compare serum androgens concentrations in the BdF with other breeds and to determine whether CAG repeats length and plasma androgens concentrations are correlated. MATERIALS AND METHODS: Androgens were measured in 46 BdF and in 53 other dog breed. Length of CAG-I and CAG-III repeats were measured in 41 BdF and correlated with androgen levels. RESULTS: In the BdF group shorter CAG-I and longer CAG-III repeat lengths were associated with lower androgen concentrations. CONCLUSION: As the shorter CAG-I repeat is associated with an increased PCA risk, higher androgen concentrations may protect against the development and progression of PCA.

U. Rub, K. Burk, D. Timmann, W. den Dunnen, K. Seidel, K. Farrag, E. Brunt, H. Heinsen, R. Egensperger, A. Bornemann, S. Schwarzacher, H.-W. Korf, L. Schols, J. Bohl and T. Deller (2012) Neuropathology and Applied Neurobiology 38, 665680 Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights Aims: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. Methods: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. Results: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. Conclusions: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

BACKGROUND: The Bouvier des Flandres (BdF) dog is predisposed to develop prostate carcinoma (PCA). In humans, ethnic groups with higher prevalence of PCA have higher serum androgens concentrations and shorter polyglutamine (CAG) repeat lengths in the androgen receptor (AR) gene. In dogs, shorter CAG-I lengths are associated with increased PCA risk. OBJECTIVE: To compare serum androgens concentrations in the BdF with other breeds and to determine whether CAG repeats length and plasma androgens concentrations are correlated. MATERIALS AND METHODS: Androgens were measured in 46 BdF and in 53 other dog breed. Length of CAG-I and CAG-III repeats were measured in 41 BdF and correlated with androgen levels. RESULTS: In the BdF group shorter CAG-I and longer CAG-III repeat lengths were associated with lower androgen concentrations. CONCLUSION: As the shorter CAG-I repeat is associated with an increased PCA risk, higher androgen concentrations may protect against the development and progression of PCA.

Background: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.Objectives: To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations.Design, Setting, and Participants: We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.Results: The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families ( of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).Conclusions: The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.

Polyglutamine (PolyQ) aggregates are a hallmark of several severe neurodegenerative diseases, expanded CAG-repeat diseases in which inheritance of an expanded polyQ sequence above a pathological threshold is associated with a high risk of disease. Application of vibrational circular dichroism (VCD) reveals that these PolyQ fibril aggregates exhibit a chiral supramolecular organization that is distinct from the supramolecular organization of previously observed amyloid fibrils. PolyQ fibrils grown from monomers with Q repeats 35 and above (Q⩾35) exhibit approximately 10-fold enhancement of the same VCD spectrum compared to the already enhanced VCD of fibrils formed from Q repeats 30 and below (Q⩽30).