Increase in wasteosomes (corpora amylacea) in frontotemporal lobar degeneration with specific detection of tau, TDP‑43 and FUS pathology

Abstract

Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in someneurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaningmechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobardegeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLDproteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration.Wasteosome scores were obtained in various brain regions from 124 post‑mortem diagnosed sporadic FTLD patients,including 75 participants with tau (FTLD‑tau), 42 with TAR DNA‑binding protein 43 (FTLD‑TDP), and 7 with Fusedin Sarcoma (FTLD‑FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brainregion for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables,and multiple regressions explored associations with age at death and disease duration. Double immunofluorescencestudies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulationof wasteosomes than control subjects, especially those with FTLD‑FUS. Unlike FTLD‑TDP and control subjects, wasteo‑some accumulation did not increase with age in FTLD‑tau and FTLD‑FUS. Cases with shorter disease duration in FTLD‑tau and FTLD‑FUS seemed to exhibit higher wasteosome quantities, whereas FTLD‑TDP appeared to show an increasewith disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated‑TDP‑43in the periphery of isolated wasteosomes in some patients with FTLD‑tau and FTLD‑TDP, respectively. Central inclu‑sions of FUS were observed in a higher number of wasteosomes in FTLD‑FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD‑FUS. Detecting these proteins, particularlyFUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD.