A recent study from the Molecular Neurodegeneration lab led by Wiep Scheper (FGA) has been published in Science Advances. In this work first author Jasper Smits and colleagues from FGA and MCN elucidated a previously unknown intrinsic resilience mechanism against tau aggregation in neurons.
In Alzheimer’s disease (AD) intraneuronal aggregation of the protein tau leads to neurodegeneration. Previous studies showed that tau aggregation reduces protein synthesis and that restoring protein synthesis improves neuronal survival. At the same time, tau aggregation is also accompanied by the presence of lysosomal structures known as granulovacuolar degeneration bodies (GVBs) in AD patients. Up until now, it remained unclear whether these structures contribute to neurodegeneration or instead protect the neuron.
In the current study -supported by Hersenstichting/Coby van Nieuwkerkfonds and NWO-, Jasper and co-authors demonstrate that the kinase CK1δ plays a key role in GVB formation: inhibiting CK1δ almost completely ablated GVB formation, while overexpression of CK1δ nearly doubled the amount of GVB+ neurons. They furthermore showed that the accumulation of CK1δ and other cargo into the GVB depends on the autophagic machinery.
Moreover, the researchers showed that also in their model, tau aggregation drives neurodegeneration, which is paired with a reduction in protein synthesis. They show that the increased protein synthesis in GVB+ neurons is most likely due to an increase in ribosomal biogenesis factors, absent in GVB- neurons. The researchers also found that tau aggregation reduces the immediate-early-gene response of cFOS and ARC; 2 proteins important in LTP and memory formation. Again, GVB+ neurons showed a similar response as neurons without tau aggregation.
This study identified CK1δ as an upstream regulator of GVB formation that confers a protective neuron-specific stress response to tau pathology, offering new insights into neuronal resilience upon tau aggregation. This may represent a promising avenue for therapeutic strategies by enhancing neuronal resilience pathways.