The RNA-binding protein TDP-43 forms pathological aggregates in the brains of patients with amyotrophic lateral sclerosis and frontotemporal dementia. Since its discovery in 2006 and the initial observations that unlike most of the other proteins that accumulate in other neurodegenerative diseases, most TDP-43 aggregates do not stain with amyloidophilic dyes, a debate in the field has been whether TDP-43 aggregates in disease adopt amyloid fibrillar structures or not. This debate has become even stronger last year, when a number of studies identified amyloid fibrils of another protein, called TMEM106B, in tissues of patients with ALS and FTD, but also those of patients with other neurodegenerative diseases, as well as old subjects without evidence of a neurodegenerative condition. In previous work, the team has used ALS patient tissues, as well as tissues from FTLD-TDP with the subtype B to resolve the structures of TDP-43 aggregates and they reported that they adopt a fibrillar structure of double-spiral-shaped fold with no obvious structural distinction between ALS and FTD type B. In the current study Arseni et al resolve TDP-43 filament structures from three patient brain samples with type-A FTLD-TDP using cryo-EM. They show that type A TDP-43 fibrils have a district structure from the ALS and FTLD-TDP fibrils. Using mass spectrometry, the team identifies two new post-translational modifications of assembled TDP-43, citrullination, and monomethylation of R293, which they propose to facilitate the formation of the fibrils. This is an excellent piece of work with high impact on the field since these data unambiguously show that 1. TDP-43 accumulations in patients adopt an amyloid fibrillary structure and 2. TDP-43 fibrils from different disease subtypes have distinct molecular structures. This is in line with data from other neurodegenerative diseases and suggests that the different fibrillar structures trigger different toxic pathways in the patients with different disease subtypes, in agreement with the notion of “TDP-43 strains” that was previously proposed. For this reason, I enthusiastically recommend the work for publication in Nature, after revision of the current manuscript to address the following points of criticism.