A model for the dynamics of expanded CAG repeat alleles: ATXN2 and ATXN3 as prototypes.

Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.

Dissecting the role of glutamine in seeding peptide aggregation.

Poly glutamine and glutamine-rich peptides play a central role in a plethora of pathological aggregation events. However, biophysical characterization of soluble oligomers -the most toxic species involved in these processes- remains elusive due to their structural heterogeneity and dynamical nature. Here, we exploit the high spatio-temporal resolution of coarse-grained simulations as a computational microscope to characterize the aggregation propensity and morphology of a series of polyglutamine and glutamine-rich peptides. Comparative analysis of ab-initio aggregation pinpointed a double role for glutamines. In the first phase, glutamines mediate seeding by pairing monomeric peptides, which serve as primers for higher-order nucleation. According to the glutamine content, these low molecular-weight oligomers may then proceed to create larger aggregates. Once within the aggregates, buried glutamines continue to play a role in their maturation by optimizing solvent-protected hydrogen bonds networks.

The Role of the Cerebellum in Huntington's Disease: a Systematic Review.

Huntington's disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.

Aplicaciones de terapias de reemplazo celular al tratamiento de enfermedades poliglutamínicas / Applications of cell replacement therapies to the treatment of poly-glutamine diseases

Se realizó una revisión de la literatura especializada con el objetivo de evaluar el estado del arte en cuanto a la aplicación de terapias de reemplazo celular en enfermedades poliglutamínicas. Se consultaron las bases de datos HighWire y PubMed, con el uso de descriptores y operadores booleanos. Se recuperaron 84 artículos sobre la temática, publicados en revistas con un factor de impacto promedio de 5,42. Se discuten los estudios experimentales y pre-clínicos realizados con relación a terapias de reemplazo celular en enfermedades poliglutamínicas. Se demuestra la efectividad del uso de células madre de distintas fuentes en el mejoramiento de la función motora en modelos experimentales de enfermedades poliglutamínicas. Se revela la necesidad de realizar estudios multicéntricos a mediano y largo plazos, para la evaluación de los efectos terapéuticos de las terapias de reemplazo celular en enfermedades poliglutamínicas.

A review of the specialized literature was carried out with the aim of evaluating the state of the art regarding the application of cell replacement therapies in polyglutamine diseases. The HighWire and PubMed databases were consulted, with the use of Boolean descriptors and operators. 84 articles were retrieved on the subject, published in journals with an average impact factor of 5.42. The experimental and pre-clinical studies carried out in relation to cell replacement therapies in polyglutamine diseases are discussed. The effectiveness of the use of stem cells from different sources in the improvement of motor function in experimental models of polyglutamine diseases is demonstrated. The need to perform multicenter studies in the medium and long term is revealed, for the evaluation of the therapeutic effects of cell replacement therapies in polyglutamine diseases.

Cancer in Machado-Joseph disease patients-low frequency as a cause of death.

Since polyglutamine diseases have been related to a reduced risk of cancer, we aimed to study the 15 years cumulative incidence of cancer (CIC) (arm 1) and the proportion of cancer as a cause of death (arm 2) in symptomatic carriers of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). SCA3/MJD and control individuals from our state were invited to participate. A structured interview was performed. CIC as published by the Brazilian National Institute of Cancer, was used as populational control. Causes of death were obtained from the Public Information System on Mortality. We interviewed 154 SCA3/MJD patients and 80 unrelated controls: CIC was 7/154 (4.5%) and 5/80 (6.3%), respectively. The interim analysis for futility showed that the number of individuals required to detect a significant difference between groups (1938) would be three times larger than the existing local SCA3/MJD population (625), for an absolute risk reduction of 1.8%. Then this study arm was discontinued due to lack of power. In the same period, cancer was a cause of death in 9/101 (8.9%) SCA3/MJD and in 52/202 (26.2%) controls, with an absolute reduction risk of 17.3% (OR 0.27, 95%CI 0.13 to 0.58, p = 0.01). A significant reduction of cancer as cause of death was observed in SCA3/MJD, suggesting a common effect to all polyglutamine diseases.

Genetic aspects of Huntington's disease in Latin America. A systematic review.

We aimed to present a systematic review on Huntington's disease (HD) in Latin America (LA). PubMed and LILACS were searched up to March 2015, reporting confirmed HD cases in LA. Case series, cross-sectional, case-control, and prospective studies were included. From 534 communications, 47 were eligible. Population-based studies were not found; minimal prevalence of 0.5-4/100,000 was estimated for Venezuela and Mexico. Geographical isolates were well characterized in Venezuela and in Peru. CAG repeats at HTT gene varied between 7-33 and 37-112 in normal and expanded alleles, respectively. Intermediate alleles were found in 4-10% of controls. Ages at onset and the expanded CAG repeats correlated with r from - 0.55 to -0.91. While haplotype patterns of Venezuelan and Brazilian chromosomes were similar to those observed in Europeans, haplotypes from Peruvian HD patients did not match the same pattern. The limited number of papers found suggests that HD is poorly diagnosed in LA. Minimal prevalence seemed to be halfway between those of Caucasians and Asians. Range of CAG repeats was similar to those of Europeans. Haplotype studies indicate that majority of HD patients might be of Caucasian descent; an Asian origin for some Peruvian patients was proposed.

Occupational therapy in spinocerebellar ataxia type 3: an open-label trial

Occupational therapy (OT) is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3) patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF), was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn), age, age of onset, or neurological scores at baseline (Spearman test). Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.