Necrosome-positive granulovacuolar degeneration is associated with TDP-43 pathological lesions in the hippocampus of ALS/FTLD cases

Aim Granulovacuolar degeneration (GVD) in Alzheimer's disease (AD) involves the necrosome, which is a protein complex consisting of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3 and phosphorylated mixed lineage kinase domain-like protein (pMLKL). Necrosome-positive GVD was associated with neuron loss in AD. GVD was recently linked to theC9ORF72mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with transactive response DNA-binding protein (TDP-43) pathology (FTLD-TDP). Therefore, we investigated whether GVD in cases of the ALS-FTLD-TDP spectrum (ALS/FTLD) shows a similar involvement of the necrosome as in AD, and whether it correlates with diagnosis, presence of protein aggregates and cell death in ALS/FTLD. Methods We analysed the presence and distribution of the necrosome inpost-mortembrain and spinal cord of ALS and FTLD-TDP patients (n = 30) with and without theC9ORF72mutation, and controls (n = 22). We investigated the association of the necrosome with diagnosis, the presence of pathological protein aggregates and neuronal loss. Results Necrosome-positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and was associated with hippocampal TDP-43 inclusions as the main predictor of the pMLKL-GVD stage, as well as with the Braak stage of neurofibrillary tangle pathology. The central cortex and spinal cord, showing motor neuron loss in ALS, were devoid of any accumulation of pRIPK1, pRIPK3 or pMLKL. Conclusions Our findings suggest a role for hippocampal TDP-43 pathology as a contributor to necrosome-positive GVD in ALS/FTLD. The absence of necroptosis-related proteins in motor neurons in ALS argues against a role for necroptosis in ALS-related motor neuron death.

Automated summary

The presence of necrosome-positive GVD in ALS/FTLD patients was primarily linked to hippocampal TDP-43 pathology, while motor neuron loss in ALS showed no accumulation of necroptosis-related proteins.