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

Lee Y
Brown University
January 1, 2022
Brain
https://pubmed.ncbi.nlm.nih.gov/34928329

This article is currently being updated. View its version on PubMed.

https://pubmed.ncbi.nlm.nih.gov/34928329

Research summary

Loss-of-function of the X-linked Na⁺/H⁺ exchanger NHE6 (Slc9a6) causes Christianson syndrome. In NHE6-null male rat, CRISPR‑Cas9 deletion of exon 7 induces early lysosomal deficiency followed by autophagy dysfunction, gliosis, Purkinje and pyramidal cell loss; aged rats develop endogenous amyloid‑β and tau aggregation in cortex and hippocampus.

Key outcome of the study

Early lysosome and autophagy defects precede neurodegeneration; cerebellar Purkinje cell loss at early age; cortical/hippocampal pyramidal cell degeneration emerging later; aged rats develop amyloid‑β and tau deposits endogenously without transgenes

Model

Slc9a6⁻/⁻ rat (NHE6‑null CRISPR‑Cas9 rat model) — robust model exhibiting amyloid‑β and tau pathology (Christianson syndrome model)

TARGET:
Slc9a6
Synonyms:
NHE6, SLC9A6

Keywords

Neurodegeneration; Christianson syndrome; lysosomal dysfunction; amyloid‑β; tau aggregation; Alzheimer‑relevant mechanisms

Technical specifications

CRISPR‑Cas9 deletion of exon 7 in rat Slc9a6; in vivo lifespan analysis; histopathology; immunostains for GM2, p62, ubiquitin, AT8/tau; biochemical fractionation of amyloid‑β and tau

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