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. 2024 Jun 19;147(1):104.
doi: 10.1007/s00401-024-02753-7.

Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies

John L Robinson  1 , EunRan Suh #  1 , Yan Xu  1 , Howard I Hurtig  2 , Lauren Elman  2 , Corey T McMillan  2 , David J Irwin  2 , Sílvia Porta  3 , Vivianna M Van Deerlin  4 , Edward B Lee  5
Affiliations

Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies

John L Robinson et al. Acta Neuropathol. .

Abstract

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

Keywords: ALS; Annexin A11; FTLD–TDP; Neurodegenerative disease; TDP-43.

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Figures

Fig. 1
Fig. 1
Annexin A11 aggregation in FTLD–TDP Type C. Annexin A11 antibody specifically labels canonical Type C pathology including a long DNs in cortical regions and compact NCIs in the dentate gyrus (representative images, cases #16 and 22; scale bar = 50 µm). b Distribution and severity of annexin A11 inclusions closely matched the distribution and severity of TDP-43 inclusions in FTLD–TDP Type C cases. Shown is the average semi-quantitative regional burden (severity score) for each pathology from four cases (cases #16, 22, 33, 48). c Double immunofluorescence against annexin A11 and phosphorylated TDP-43 (pTDP-43) reveals abundant co-localization of the two proteinopathies in cortex (case #25, upper row). Case #23 showed annexin A11 positive neurites in the molecular layer of the hippocampus that were less prominent by TDP-43 staining (lower row; scale bar = 50 µm)
Fig. 2
Fig. 2
Spectrum of annexin A11 aggregation in TDP-43 proteinopathies. Annexin A11 pathology paralleled the morphology of the TDP-43 inclusions present in each disease. a In LATE-NC (upper row, left), annexin A11 inclusions were observed as globular NCIs or small neurites (case #11). In a case of FTLD-TDP Type A with GBA p.N409S (upper row, right), there were abundant compact NCIs in the superficial layers of the cortex (case #3). In a Type B case with a C9orf72 expansion (lower row, left), annexin A11 positive NCIs in superficial and deep layers of the cortex were noted (case #4). In a TBK1 variant (lower row, right), annexin A11 positive crescent-shaped and ring-like NCIs were apparent (case #6; scale bar = 50 µm). b Distribution of annexin A11 inclusions closely matched the distribution of TDP-43 inclusions in LATE-NC but was typically less severe. Shown is the average semi-quantitative regional aggregate burden from all annexin A11 positive LATE-NC cases (cases #8–15). c Double immunofluorescence against annexin A11 and TDP-43 reveals co-localization of the two proteinopathies in the cerebrum (case #7, upper row) and occasional comingling within motor neurons (middle row), although motor neuron aggregates in ALS were often TDP-43 positive and annexin A11 negative (lower row). Scale bar = 20 µm, insert 5 µm
Fig. 3
Fig. 3
Annexin A11 pathology in ALS due to ANXA11 p.G38R. a Annexin A11 positive inclusions were moderate to severe in amount, comprised of NCIs in the motor cortex (scale bar = 100 µm), hippocampus and striatum (scale bar = 50 µm), with rare skein-like spinal motor neuron inclusions (scale bar = 10 µm). b By double immunofluorescence, annexin A11 pathology was typically ubiquitin positive (scale bar = 20 µm). c Many annexin A11 aggregates appeared to be TDP-43 positive such as NCIs in the dentate gryus (upper row, scale bar = 20 µm). Rare annexin A11 positive spinal motor neuron inclusions were observed that were TDP-43 positive (middle row, scale bar = 10 µm), but many spinal motor neuron inclusions were TDP-43 positive and annexin A11 negative (lower row, scale bar = 20 µm)
Fig. 4
Fig. 4
Vacuolar annexinopathy in FTLD-U due to ANXA11 p.P75S. a H&E stained sections revealed severe striatal degeneration with prominent vacuolization of the putamen (upper row, scale bars = 200, 50 and 100 µm, respectively), but with preservation of the substantia nigra (scale bar = 200 µm). GFAP stain highlights reactive astrocytosis. Ubiquitin and p62 immunohistochemistry revealed abundant neuritic inclusions (middle row). Annexin A11 aggregates affected many regions of the brain, including a high burden of dystrophic neurites in striatum (middle row), globular NCIs in the pons, dystrophic neurites in neocortex, and both dystrophic neurites and NCIs in the hippocampus (lower row, scale bar = 50 µm). b Double immunofluorescence showed striatal annexin A11 aggregates to be strongly ubiquitin positive (upper row) compared to neocortical regions (parietal cortex, lower row; scale bar = 50 µm)
Fig. 5
Fig. 5
Biochemical analyses of annexin A11 and TDP-43 in FTLD–TDP and ANXA11 variant cases. Immunoblots against annexin A11 and TDP-43 of sarkosyl-insoluble fractions from ALS, FTLD–TDP and ANXA11 variant cases. For panels (a) and (b), lane 1 is an FTLD–TDP Type A case without annexinopathy, lanes 2–4 are FTLD–TDP Type B cases without annexinopathy where the asterisk denotes a case with concurrent ALS, and lanes 5–10 correspond to annexinopathy cases in this study (cases #26, 43, 18, 17, 2 & 1, respectively). a Annexin A11 positive bands were detected in all Type C cases and both ANXA11 variant cases at ~ 56 kDa and between 20 and 25 kDa (**), that were not detected in FTLD–TDP Type A or Type B cases without annexinopathy. b All FTLD–TDP cases and the ALS p.G38R variant show phosphorylated full-length TDP-43-positive bands at ~ 43 kDa and truncated TDP-43 between ~ 23 and 25 kDa (***). Truncated TDP-43 was not detected in the ANXA11 p.P75S variant case. For panels (c) and (d), lanes 1 and 2 are frontal cortex (FCX) while lanes 3 to 6 are amygdalar region (AMY) where lanes 1 to 6 correspond to cases #4, 17, 6, 7, 41 and 19, respectively. c Annexin A11 positive bands at ~ 56 kDa and between 20 and 25 kDa (**) were detected in all cases. d Same fractions were also positive for phosphorylated full-length TDP-43 at ~ 43 kDa and truncated TDP-43 between ~ 23 and 25 kDa (***)
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