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Background: Loss‐of‐function mutations in the X‐linked endosomal Na+/H+ Exchanger 6 (NHE6) cause Christianson syndrome (CS) in males. CS involves endosome dysfunction leading to early cerebellar degeneration, as well as later‐onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in postmortem studies. In addition, there is reported evidence of modulation of amyloid beta (Aβ) levels in experimental models wherein NHE6 expression was targeted. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously‐expressed Aβ and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously‐expressed (non‐transgenic) tau or Aβ. Method: We generated an NHE6‐null rat model of CS using CRISPR‐Cas9 genome‐editing technologies to study neurodegeneration in CS and the possibility of Aβ and tau pathology. Result: Using this novel rat model, we were able to follow the sequence of pathogenic events in CS. NHE6‐null rats demonstrate an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observe biochemical and in situ evidence of both Aβ and tau aggregation in the aged NHE6‐null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observe tau deposition in both neurons and glia, as has been reported in CS postmortem studies previously. Conclusion: This new model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously‐expressed Aβ and tau. This NHE6‐null rat will serve as a new robust model for CS. Furthermore, these studies provide evidence for linkages between endo‐lysosome dysfunction and neurodegeneration involving protein aggregations, including Aβ and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's Disease and related dementias. [ABSTRACT FROM AUTHOR]

The crystal structure of the unbound form of HIV-1 subtype A protease (PR) has been determined to 1.7 Å resolution and refined as a homodimer in the hexagonal space group P61 to an Rcryst of 20.5%. The structure is similar in overall shape and fold to the previously determined subtype B, C and F PRs. The major differences lie in the conformation of the flap region. The flaps in the crystal structures of the unbound subtype B and C PRs, which were crystallized in tetragonal space groups, are either semi-open or wide open. In the present structure of subtype A PR the flaps are found in the closed position, a conformation that would be more anticipated in the structure of HIV protease complexed with an inhibitor. The amino-acid differences between the subtypes and their respective crystal space groups are discussed in terms of the differences in the flap conformations. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor reporting the experience with a child who had deletion 13q syndrome.