TDP-43 is the principal component of neuronal inclusions in frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Since the major actions of TDP-43 derive from its RNA binding activity, determining if TDP-43 RNA targets are altered in disease will provide insight on the mechanisms of TDP-43 toxicity. RNA-immunoprecipitation studies in human HEK293T cells identified sortilin (SORT1), a neuronal progranulin (PGRN) receptor, as a TDP-43 target. Mutations in GRN are a major cause of FTLD-TDP. That TDP-43 regulates SORT1 RNA now provides a putative link between TDP-43 dysfunction and altered PGRN signaling in sporadic FTLD-TDP and ALS. Preliminary data shows that Tdp-43 regulates Sort1 mRNA splicing in murine primary neurons and mouse brain. Tdp-43 knockdown leads to the retention of 99 base pairs within intron 17 of Sort1, referred to as "exon 17b". Exon 17b is highly conserved between mouse and human, so it is very probable that human SORT1 is regulated by TDP-43. Indeed, an alternatively spliced SORT1 variant lacking exon 18 (SORT1 Ex18) was identified as a TDP-43-bound transcript in human neuroblastoma cells. It encodes a SORT1 (SORT1 Ex18) isoform with a truncated C-terminus. Given that the C-terminus is required for PGRN endocytosis, expression of SORT1 Ex18 is likely to have detrimental consequences on PGRN signaling. Likewise, Sort1+Ex17b expression may alter Pgrn function. We have shown that neurite outgrowth and branching are decreased in Pgrn-/- cortical neurons, a phenotype rescued by recombinant human PGRN. Overall, we presume there exists a bidirectional relationship between TDP-43 and SORT1/PGRN, such that abnormalities in TDP-43 promote SORT1/PGRN dysregulation and, conversely, SORT1/PGRN dysregulation causes TDP-43 pathology, thus perpetuating a neurotoxic cycle. The latter is supported by the finding that TDP-43 aggregation is attenuated in cultured cells when SORT1 is overexpressed, suggestion that loss of SORT1 function may indeed contribute to TDP-43 pathology. Our objective is thus to investigate this relationship in more detail. To this end, we will use a combination of in vitro and in vivo models to investigate: 1) the functional mechanisms underlying TDP-43-mediated SORT1 regulation;2) whether SORT1 RNA expression and/or splicing, as well as SORT1 protein expression, are altered in FTLD-TDP;3) whether various SORT1 isoforms differentially influence PGRN signaling;and 4) the influence of SORT1 isoforms on TDP-43 aggregation and toxicity.

Public Health Relevance

TDP-43 is involved in the pathogenesis of frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), yet how it causes neurodegeneration remains unclear. The goal of this project is to investigate the relationship among TDP-43, sortilin and progranulin, all of which have been implicated in FTLD-TDP. The discoveries emerging from our studies will provide insight on whether this pathway represents an attractive therapeutic target for the treatment of FTLD-TDP and ALS.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS077402-04
Application #
8660100
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Zhang, Yong-Jie; Jansen-West, Karen; Xu, Ya-Fei et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128:505-24
Cook, Casey; Carlomagno, Yari; Gendron, Tania F et al. (2014) Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet 23:104-16
Cook, Casey; Dunmore, Judy H; Murray, Melissa E et al. (2014) Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging 35:1769-77
Gendron, Tania F; Belzil, Veronique V; Zhang, Yong-Jie et al. (2014) Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127:359-76
Belzil, Veronique V; Bauer, Peter O; Gendron, Tania F et al. (2014) Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients. Brain Res 1584:15-21
Lee, Wing C; Almeida, Sandra; Prudencio, Mercedes et al. (2014) Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency. Hum Mol Genet 23:1467-78
Bieniek, Kevin F; van Blitterswijk, Marka; Baker, Matthew C et al. (2014) Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia. JAMA Neurol 71:775-81
Carlomagno, Yari; Zhang, Yongjie; Davis, Mary et al. (2014) Casein kinase II induced polymerization of soluble TDP-43 into filaments is inhibited by heat shock proteins. PLoS One 9:e90452
Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F et al. (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043-50
Zhang, Yong-Jie; Caulfield, Thomas; Xu, Ya-Fei et al. (2013) The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum Mol Genet 22:3112-22

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