TY - JOUR
T1 - Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer's disease
AU - Monti, Giulia
AU - Kjolby, Mads
AU - Jensen, Anne Mette G
AU - Allen, Mariet
AU - Reiche, Juliane
AU - Møller, Peter L
AU - Comaposada-Baró, Raquel
AU - Zolkowski, Bartlomiej E
AU - Vieira, Cármen
AU - Jørgensen, Margarita Melnikova
AU - Holm, Ida E
AU - Valdmanis, Paul N
AU - Wellner, Niels
AU - Vægter, Christian B
AU - Lincoln, Sarah J
AU - Nykjær, Anders
AU - Ertekin-Taner, Nilüfer
AU - Young, Jessica E
AU - Nyegaard, Mette
AU - Andersen, Olav M
PY - 2021/3/16
Y1 - 2021/3/16
N2 - SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.
AB - SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.
KW - Alternative splicing
KW - Alzheimer’s disease
KW - Dendritic transcript
KW - SORL1
KW - SORLA
UR - http://www.scopus.com/inward/record.url?scp=85103144726&partnerID=8YFLogxK
U2 - 10.1186/s40478-021-01140-7
DO - 10.1186/s40478-021-01140-7
M3 - Journal article
C2 - 33726851
SN - 2051-5960
VL - 9
SP - 43
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 43
ER -