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

Abstract

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 wasrecently linked to the C9ORF72 mutation 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) showsa 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 in post‐mortem brain and spinal cord of ALS and FTLD‐TDP patients (n=30) with and without the C9ORF72 mutation, and controls (n=22). Weinvestigated the association of the necrosome with diagnosis, the presence ofpathological protein aggregates and neuronal loss. Results Necrosome‐positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and wasassociated with hippocampalTDP‐43 inclusionsas 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 ofpRIPK1, pRIPK3 or pMLKL. Conclusions Our findings suggest a role for hippocampal TDP‐43 pathologyas a contributor to necrosome‐positive GVD in ALS/FTLD. The absence of necroptosis‐related proteins in motor neurons inALS argues against a role for necroptosis in ALS‐related motor neurondeath.