RGD Reference Report - Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain. - Rat Genome Database

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Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain.

Authors: Lee, YouJin  Miller, Morgan R  Fernandez, Marty A  Berg, Elizabeth L  Prada, Adriana M  Ouyang, Qing  Schmidt, Michael  Silverman, Jill L  Young-Pearse, Tracy L  Morrow, Eric M 
Citation: Lee Y, etal., Brain. 2021 Dec 20. pii: 6470622. doi: 10.1093/brain/awab467.
RGD ID: 151664747
Pubmed: PMID:34928329   (View Abstract at PubMed)
DOI: DOI:10.1093/brain/awab467   (Journal Full-text)

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. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. 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. Therefore, to study neurodegeneration in CS and the possibility of Aβ and tau pathology, we generated an NHE6-null rat model of CS using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. 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. In summary, this experimental 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Slc9a6Ratglial cell activation  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SD-Slc9a6 em1MoroRatabnormal lysosome physiology  IMP  RGD 
Slc9a6Ratabnormal lysosome physiology  IMP  RGD 
Slc9a6 em1MoroRatabnormal lysosome physiology  IMP  RGD 
SD-Slc9a6 em1MoroRatastrocytosis  IMP  RGD 
Slc9a6Ratastrocytosis  IMP  RGD 
Slc9a6 em1MoroRatastrocytosis  IMP  RGD 
SD-Slc9a6 em1MoroRataxon degeneration  IMP  RGD 
Slc9a6Rataxon degeneration  IMP  RGD 
Slc9a6 em1MoroRataxon degeneration  IMP  RGD 
SD-Slc9a6 em1MoroRatdecreased cerebral cortex average cell area  IMP  RGD 
Slc9a6Ratdecreased cerebral cortex average cell area  IMP  RGD 
Slc9a6 em1MoroRatdecreased cerebral cortex average cell area  IMP  RGD 
SD-Slc9a6 em1MoroRatdecreased locomotor activity  IMP  RGD 
Slc9a6Ratdecreased locomotor activity  IMP  RGD 
Slc9a6 em1MoroRatdecreased locomotor activity  IMP  RGD 
SD-Slc9a6 em1MoroRatdecreased Purkinje cell number  IMP  RGD 
Slc9a6Ratdecreased Purkinje cell number  IMP  RGD 
Slc9a6 em1MoroRatdecreased Purkinje cell number  IMP  RGD 
SD-Slc9a6 em1MoroRatdecreased vertical activity  IMP  RGD 
Slc9a6Ratdecreased vertical activity  IMP  RGD 
Slc9a6 em1MoroRatdecreased vertical activity  IMP  RGD 
SD-Slc9a6 em1MoroRatenlarged lateral ventricles  IMP  RGD 
Slc9a6Ratenlarged lateral ventricles  IMP  RGD 
Slc9a6 em1MoroRatenlarged lateral ventricles  IMP  RGD 
SD-Slc9a6 em1MoroRatimpaired autophagy  IMP  RGD 
Slc9a6Ratimpaired autophagy  IMP  RGD 
Slc9a6 em1MoroRatimpaired autophagy  IMP  RGD 
SD-Slc9a6 em1MoroRatimpaired coordination  IMP  RGD 
Slc9a6Ratimpaired coordination  IMP  RGD 
Slc9a6 em1MoroRatimpaired coordination  IMP  RGD 
SD-Slc9a6 em1MoroRatincreased ganglioside level  IMP  RGD 
Slc9a6Ratincreased ganglioside level  IMP  RGD 
Slc9a6 em1MoroRatincreased ganglioside level  IMP  RGD 
SD-Slc9a6 em1MoroRatloss of cortex neurons  IMP  RGD 
Slc9a6Ratloss of cortex neurons  IMP  RGD 
Slc9a6 em1MoroRatloss of cortex neurons  IMP  RGD 
SD-Slc9a6 em1MoroRatloss of hippocampal neurons  IMP  RGD 
Slc9a6Ratloss of hippocampal neurons  IMP  RGD 
Slc9a6 em1MoroRatloss of hippocampal neurons  IMP  RGD 
SD-Slc9a6 em1MoroRatmicrogliosis  IMP  RGD 
Slc9a6Ratmicrogliosis  IMP  RGD 
Slc9a6 em1MoroRatmicrogliosis  IMP  RGD 
SD-Slc9a6 em1MoroRatshortened head  IMP  RGD 
Slc9a6Ratshortened head  IMP  RGD 
Slc9a6 em1MoroRatshortened head  IMP  RGD 
SD-Slc9a6 em1MoroRatsmall cerebellum  IMP  RGD 
Slc9a6Ratsmall cerebellum  IMP  RGD 
Slc9a6 em1MoroRatsmall cerebellum  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Slc9a6  (solute carrier family 9 member A6)
Slc9a6 em1Moro  (solute carrier family 9 member A6;CRISPR/Cas9 induced mutant1, Moro)

Strains
SD-Slc9a6 em1Moro  (NA)

Objects referenced in this article
Strain SD-Slc9a6 em1Moro/Rrrc null Rattus norvegicus

Additional Information