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. 2019 May 15;13:486. doi: 10.3389/fnins.2019.00486

Figure 2.

Figure 2

Potential and confirmed phenotypic features of C9orf72 HRE-associated microglia in FTLD/ALS. Features detected in the microglia of FTLD or ALS patient post-mortem brain are indicated in bold text. The presence of the typical C9-HRE-associated pathological hallmarks, which have previously been observed mainly in neurons, as well as other potential mechanisms, which still need to be confirmed in human patient microglia, are indicated with a question mark. Directions of sequential events are visualized with arrows. Steps requiring intracellular or intercellular translocation of molecules are indicated by dashed arrows. The different events are indicated by numbers as follows: (1) C9-HRE-containing RNA might be transcribed in microglia, forming intranuclear sense and antisense RNA foci, which may disturb RNA metabolism. (2) C9-HRE-containing RNA might be translocated into the cytosol of microglia, where it could undergo RAN translation creating potentially toxic DRPs. (3) DRPs might also be transmitted from other cell types, such as neurons, to microglia. (4) Potential disturbances in RNA metabolism as well as DRP toxicity might lead to TDP-43 pathology, which in turn could lead to defects in RNA processing in microglia. (5) Expression of poly-GA in combination with enhanced TDP-43 phosphorylation (p-TDP-43) or poly-GR expression alone in neurons might lead to downstream signals, which are recognized by adjacent microglia, leading first to enhanced CD68 and later Iba1 expression. (6) CD68 could serve as a receptor on the cell surface or localize in lysosomes. (7) Downregulation of C9orf72 might increase TREM2 and TYROBP expression, which might be a sign of M2 microglial phenotype switching and result in increased phagocytic activity. (8) Microglial C3ar1 and C1qb expression might be increased through decreased expression of C9orf72 and lead to enhanced synaptic pruning. (9) Decreased C9orf72 expression might disturb autophagy pathway, resulting in p62 accumulation and enlarged lysosomes in microglia. C1qb, complement subcomponent C1q chain B; C3ar1, complement C3a Receptor 1; CD68, cluster of differentiation 68; DRP, dipeptide repeat protein; HRE, hexanucleotide repeat expansion; Iba1, ionized calcium-binding adapter molecule 1; RAN, repeat-associated non-AUG; TDP-43, Transactive response DNA binding protein 43; TREM2, Triggering receptor expressed on myeloid cells 2; TYROBP, tyrosine kinase binding protein.