Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice.
Tuancheng FengHuan DuCha YangYa WangFenghua HuPublished in: Acta neuropathologica (2024)
TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently, TMEM106B polymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover, Tmem106b -/- PS19 mice develop significantly increased abnormalities in the neuronal cytoskeleton, autophagy-lysosome activities, as well as glial activation, compared with PS19 and Tmem106b -/- mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.
Keyphrases
- cerebrospinal fluid
- end stage renal disease
- amyotrophic lateral sclerosis
- spinal cord injury
- chronic kidney disease
- newly diagnosed
- cell death
- early onset
- type diabetes
- multiple sclerosis
- adipose tissue
- oxidative stress
- dna methylation
- peritoneal dialysis
- metabolic syndrome
- white matter
- ejection fraction
- transcription factor
- cognitive impairment
- fluorescent probe
- endoplasmic reticulum stress
- copy number
- insulin resistance
- subarachnoid hemorrhage
- wild type
- prefrontal cortex