The chaperone DNAJB6 surveils FG-nucleoporins and is required for interphase nuclear pore complex biogenesis.

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage of biomolecules across the nuclear envelope. The FG-Nups are intrinsically disordered and prone to liquid-liquid phase separation and aggregation when isolated. How FG-Nups are protected from making inappropriate interactions during NPC biogenesis is not fully understood. Here we find that DNAJB6, a molecular chaperone of the heat shock protein network, forms foci in close proximity to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Conversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and these foci are identified as herniations at the nuclear envelope. Immunoelectron tomography shows that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Loss of DNAJB6 results in the accumulation of cytosolic annulate lamellae, which are structures containing partly assembled NPCs, a feature associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG region of several FG-Nups in cells and in vitro. Together, our data show that the molecular chaperone DNAJB6 provides quality control during NPC biogenesis and is involved in the surveillance of native intrinsically disordered FG-Nups.

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). METHODS: Two authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071). RESULTS: Eleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27-33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance. CONCLUSIONS: Current evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.