Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis
Male
name=Neurology
610
/dk/atira/pure/subjectarea/asjc/2800/2804
tau Proteins
/dk/atira/pure/subjectarea/asjc/2800/2808
03 medical and health sciences
Cell Line, Tumor
Humans
Hyperphosphorylated tau
Phosphorylation
Aged
Aged, 80 and over
Neurons
0303 health sciences
Amyotrophic Lateral Sclerosis
Middle Aged
Amyotrophic lateral sclerosis
Mitochondria
Oxidative Stress
Synapses
Mitochondrial dynamics
Tau degrader
Female
Mitochondrial dysfunction
name=Cellular and Molecular Neuroscience
DOI:
10.1007/s12035-021-02557-w
Publication Date:
2021-11-10T06:02:36Z
AUTHORS (24)
ABSTRACT
AbstractUnderstanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivityin vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stressin vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.Graphical abstractpTau-S396 mis-localizes to synapses in ALS.ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentationin vitro.pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS.Reducing tau with a specific degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stressin vitro.
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