Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.
Humans
Aged
Annexins
/ genetics
Female
Male
DNA-Binding Proteins
/ genetics
Frontotemporal Lobar Degeneration
/ genetics
Middle Aged
Aged, 80 and over
TDP-43 Proteinopathies
/ pathology
Neurodegenerative Diseases
/ pathology
Amyotrophic Lateral Sclerosis
/ genetics
Inclusion Bodies
/ pathology
Brain
/ pathology
Protein Aggregation, Pathological
/ pathology
ALS
Annexin A11
FTLD–TDP
Neurodegenerative disease
TDP-43
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
19 Jun 2024
19 Jun 2024
Historique:
received:
16
04
2024
accepted:
10
06
2024
revised:
09
06
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
19
6
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38896345
doi: 10.1007/s00401-024-02753-7
pii: 10.1007/s00401-024-02753-7
doi:
Substances chimiques
Annexins
0
TARDBP protein, human
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104Subventions
Organisme : NIA NIH HHS
ID : P30AG072979
Pays : United States
Organisme : NIA NIH HHS
ID : P01AG066597
Pays : United States
Organisme : NIA NIH HHS
ID : U19AG062418
Pays : United States
Organisme : NIA NIH HHS
ID : RF1AG065341
Pays : United States
Informations de copyright
© 2024. The Author(s).
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