Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease.

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model.

The Homogeneous Azorean Machado-Joseph Disease Cohort: Characterization and Contributions to Advances in Research.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia worldwide. MJD is characterized by late-onset progressive cerebellar ataxia associated with variable clinical findings, including pyramidal signs and a dystonic-rigid extrapyramidal syndrome. In the Portuguese archipelago of the Azores, the worldwide population cluster for this disorder (prevalence of 39 in 100,000 inhabitants), a cohort of MJD mutation carriers belonging to extensively studied pedigrees has been followed since the late 1990s. Studies of the homogeneous Azorean MJD cohort have been contributing crucial information to the natural history of this disease as well as allowing the identification of novel molecular biomarkers. Moreover, as interventional studies for this globally rare and yet untreatable disease are emerging, this cohort should be even more important for the recruitment of trial participants. In this paper, we profile the Azorean cohort of MJD carriers, constituted at baseline by 20 pre-ataxic carriers and 52 patients, which currently integrates the European spinocerebellar ataxia type 3/Machado-Joseph disease Initiative (ESMI), a large European longitudinal MJD cohort. Moreover, we summarize the main studies based on this cohort and highlight the contributions made to advances in MJD research. Knowledge of the profile of the Azorean MJD cohort is not only important in the context of emergent interventional trials but is also pertinent for the implementation of adequate interventional measures, constituting relevant information for Lay Associations and providing data to guide healthcare decision makers.