Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology.
Neuron
; 107(3): 496-508.e6, 2020 08 05.
Article
en En
| MEDLINE
| ID: mdl-32526197
ABSTRACT
Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-ß effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-ß and TMEM106B on TDP-43 aggregation in older adults.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Envejecimiento
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Regulación de la Expresión Génica
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Proteinopatías TDP-43
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Factores de Empalme de ARN
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Progranulinas
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Proteínas de la Membrana
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Proteínas del Tejido Nervioso
Tipo de estudio:
Etiology_studies
/
Incidence_studies
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Observational_studies
/
Risk_factors_studies
Límite:
Aged
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Aged80
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Female
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Humans
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Male
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2020
Tipo del documento:
Article