- Biology and Pathophysiology of TDP-43 in ALS-FTD.
Since the discovery of the first gene linked to familial ALS in 1993, mutations in the gene encoding TDP-43 as the next major gene in ALS was uncovered 15 years later. The discovery of TDP-43 proteinopathy in ALS and FTD provided the opportunity to clarify disease mechanism affecting nearly all cases of ALS and large proportion of FTD. Nearly a decade later, the function of TDP-43 or its pathogenic contribution to ALS-FTD remain largely elusive. Since the function of this RNA binding protein remained incompletely known, we first assessed the physiological role of TDP-43 using gene targeting strategy and showed that TDP-43 is an essential gene required for embryonic development. TDP-43 is tightly regulated and we showed in mice lacking one allele of Tdp-43, the level of this RNA binding protein is maintained at normal levels, consistent with the notion that TDP-43 is auto-regulated. We further showed that TDP-43 is also required in adulthood, as deletion of TDP-43 after development in mice led to down-regulation of an important gene (Tbc1d1) that’s critical for metabolism. To assess the role of TDP-43 in the nervous system, we conditionally deleted TDP-43 in either the forebrains or spinal cords of mice and showed that these knockout mice exhibit age dependent neurodegeneration, supporting the notion that loss of TDP-43, as reflected in clearance of nuclear TDP-43 in ALS-FTD, could contribute to neurodegeneration in disease. Most recently, using RNA-seq transcriptome analysis in our cell model lacking Tdp-43, we discovered that TDP-43 serves as a repressor of non-conserved cryptic exons and loss of such function is compromised in brains of ALS-FTD. Moreover, we showed that TDP-43 is a founding member of a family of RNA binding proteins, including PTBP1 and PTBP2, which serve to repress cryptic exons. Importantly, we found that there exists a set of cell type specific TDP-43 cryptic exons, suggesting the possibility of identifying human neuronal specific TDP-43 targets as biomarkers for ALS-FTD.
- Chiang, P., Ling, J., Jeong, Y.H., Price, D.L., Aja, S.M. & Wong, P.C. (2010). Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. PNAS, 107(37), 16320-16324.
- Ling, J.P., Pletnikova, O., Troncoso, J.C. & Wong, P.C. (2015). TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science, 349(6248), 650-655.
- Ling, J.P., Chhabra, R., Merran, J.D., Schaughency, P.M., Wheelan, S.J., Corden, J.L. & Wong, P.C. (2016). PTBP1 and PTBP2 repress nonconserved cryptic exons. Cell Reports, 17(1), 104-113.
- Jeong, Y.H., Ling, J.P., Lin, S.Z., Donde, A.N., Braunstein, K.E., Majounie, E., Traynor, B.J., LaClair, K.D., Lloyd, T.E. & Wong, P.C. (2017). Tdp-43 cryptic exons are highly variable between cell types. Molecular Neurodegeneration, 12(13).
- Validation of TDP-43 splicing repression as a therapeutic target.
Alzheimer’s Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset, including ALS-FTD or mixed etiology dementias such as Alzheimer’s disease (AD) with TDP-43 pathology. Recent studies in human disease support the notion that loss of TDP-43 splicing repression contributes to neuron loss and cognitive deficits in ADRD. However, it is not known whether splicing repression is a major role of TDP-43 in neurons and whether targeting this function represents a viable therapeutic strategy. We tested the notion that loss of TDP-43 repression in neurons represents a major determinant contributing to neurodegeneration occurring in these human disorders. We showed that AAV9-mediated delivery of mice lacking TDP-43 in neurons of a chimeric repressor (AAV9-CTR), ameliorated degeneration of neurons. Correlating with such rescue of these cells, we showed that aberrant splicing repression is normalized in AAV9-CTR treated mice. Our findings establish that splicing repression is a major role of TDP-43 in neurons and validate TDP-43 splicing repression as an attractive therapeutic target for human disease with TDP-43 pathology.
- Sun M, Bell W, LaClair KD, Ling JP, Han H, Kageyama Y, Pletnikova O, Troncoso JC, *Wong PC and *Chen LL (2017) Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. Acta Neuropathologica 133:923-931. PMC5444385 * equal contribution
- Donde A, SunM, JeongYH, WenX, LingJ, Lin S, BraunsteinK, NieS, WangS, ChenL and Wong PC (2019). Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43. Autophagy, July 7 (doi: 10.1080/15548627.2019.1635379).
- Donde A, Sun M, Ling JP, Braunstein KE, Pang B, Wen X, Cheng X, Chen L and Wong PC (2019). Splicing repression is a major function of TDP‑43 in motor neurons. Acta Neuropathologica July 22, (doi.org/10.1007/s00401-019-02042-8).
- Loss of TDP-43 splicing repression in skeletal muscle of Inclusion Body Myositis.
Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50 and IBM muscle biopsies exhibit nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative disease. As nuclear loss of TDP-43 in neurons causes inclusion of cryptic exons, our recent work showed that loss of TDP-43 splicing repression occurs in skeletal muscle of IBM patients. This work provides the foundation for development of a prognostic biomarker and novel therapeutic strategy for IBM.
- Britson KA, Ling JP, Braunstein KE, Montagne J, Kastenschmidt J, Tsao W, Russel1 KA, Reed N, Wagner KR, Ostrow LW, Corse AM, Mammen AL, Villalta A, Larman HB, Wong PC* and Lloyd TE*: Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis. Science Translational Medicine 14, eabi9196, January 19, 2022. *co-corresponding author
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