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.
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.
|Lee, Chris W; Stankowski, Jeannette N; Chew, Jeannie et al. (2017) The lysosomal protein cathepsin L is a progranulin protease. Mol Neurodegener 12:55|
|Mohagheghi, Fatemeh; Prudencio, Mercedes; Stuani, Cristiana et al. (2016) TDP-43 functions within a network of hnRNP proteins to inhibit the production of a truncated human SORT1 receptor. Hum Mol Genet 25:534-45|
|Zhang, Yong-Jie; Gendron, Tania F; Grima, Jonathan C et al. (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci 19:668-677|
|Kramer, Nicholas J; Carlomagno, Yari; Zhang, Yong-Jie et al. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science 353:708-12|
|Tian, Feng; Yang, Wenlong; Mordes, Daniel A et al. (2016) Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging. Nat Commun 7:13283|
|Jiang, Jie; Zhu, Qiang; Gendron, Tania F et al. (2016) Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron 90:535-50|
|Prudencio, Mercedes; Belzil, Veronique V; Batra, Ranjan et al. (2015) Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat Neurosci 18:1175-82|
|Oprea, Tudor I; Sklar, Larry A; Agola, Jacob O et al. (2015) Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases. PLoS One 10:e0142182|
|Agola, Jacob O; Sivalingam, Daniel; Cimino, Daniel F et al. (2015) Quantitative bead-based flow cytometry for assaying Rab7 GTPase interaction with the Rab-interacting lysosomal protein (RILP) effector protein. Methods Mol Biol 1298:331-54|
|Chew, Jeannie; Gendron, Tania F; Prudencio, Mercedes et al. (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348:1151-4|
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