Deletion of chromosome 21 and normal intelligence: molecular definition of the lesion

Summary Application of a method for the fine structure analysis of unbalanced chromosomal rearrangements using quantitative Southern blot analysis has established that an individual of normal intelligence and largely normal appearance has a significant interstitial deletion of chromosome 21. Using high resolution cytogenetic analysis and molecular analysis with five single copy DNA sequences unique to chromosome 21 and a probe for human SOD1 (CuZn, Superoxide dismutase), we find that the deletion extends from the border of bands 21q11.1–11.2 and extends to the border of bands 21q21.2–q21.3. The latter border is established molecularly by the presence of two copies of SOD1, previously mapped to band 21q22.1, and of four single copy sequences known to be located distal to this region. The presence of SOD1 was confirmed by enzyme dosage analysis. These findings demonstrate that deletion of close to 20,000kb of autosomal material is compatible with normal intelligence. Further, they suggest that chromosome 21 may include a large region of relative developmental neutrality whose molecular basis may now be investigated. Because of the limits of even high resolution cytogenetic analysis, fine structure molecular analyses of this type will be necessary to reliably detect and define similar small chromosomal deletions or insertions. The molecular definition of such aneuploidy provides the basis for increasing the resolution of the human physical genetic map.     

The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy

Accumulation of α-synuclein is a main underlying pathological feature of Parkinson’s disease and α-synucleinopathies, for which lowering expression of the α-synuclein gene (SNCA) is a potential therapeutic avenue. Using a cell-based luciferase reporter of SNCA expression we performed a quantitative high-throughput screen of 155,885 compounds and identified A-443654, an inhibitor of the multiple functional kinase AKT, as a potent inhibitor of SNCA. HEK-293 cells with CAG repeat expanded ATXN2 (ATXN2-Q58 cells) have increased levels of α-synuclein. We found that A-443654 normalized levels of both SNCA mRNA and α-synuclein monomers and oligomers in ATXN2-Q58 cells. A-443654 also normalized levels of α-synuclein in fibroblasts and iPSC-derived dopaminergic neurons from a patient carrying a triplication of the SNCA gene. Analysis of autophagy and endoplasmic reticulum stress markers showed that A-443654 successfully prevented α-synuclein toxicity and restored cell function in ATXN2-Q58 cells, normalizing the levels of mTOR, LC3-II, p62, STAU1, BiP, and CHOP. A-443654 also decreased the expression of DCLK1, an inhibitor of α-synuclein lysosomal degradation. Our study identifies A-443654 and AKT inhibition as a potential strategy for reducing SNCA expression and treating Parkinson’s disease pathology.     

Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by ataxia, seizures, and anticipation. It is caused by an expanded ATTCT pentanucleotide repeat in intron 9 of a novel gene, designated "SCA10." The ATTCT expansion in SCA10 represents a novel class of microsatellite repeat and is one of the largest found to cause human diseases. The expanded ATTCT repeat is unstably transmitted from generation to generation, and an inverse correlation has been observed between size of repeat and age at onset. In this multifamily study, we investigated the intergenerational instability, somatic and germline mosaicism, and age-dependent repeat-size changes of the expanded ATTCT repeat. Our results showed that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission resulted in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat.