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Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia. Electronic supplementary material The online version of this article (doi:10.1007/s13311-015-0338-x) contains supplementary material, which is available to authorized users.

TDP-43 and TDP-43 Proteinopathy, Paragraph 1: BIn the nucleus, TDP-43 plays a critical role in regulating RNA splicing, as well as modulating microRNA biogenesis [8, 9].^ Reference 9 should be: Kawahara Y, Mieda-Sato A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci U S A. 2012;109(9):3347-52. doi:10.1073/pnas.1112427109. TDP-43 and TDP-43 Proteinopathy, Paragraph 1: BIn addition to TDP-43 RNA, TDP-43 regulates the splicing and stability of a large number of other transcripts [10, 12–15], and thus influences diverse cellular processes.^ Reference 13 should be: Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C et al. TDP-43 is a human low molecular weight neurofilament (hNFL) mRNAbinding protein. Mol Cell Neurosci. 2007;35(2):320-327. Reference 14 should be: Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 2001;20(7):1774-84. TDP-43 and TDP-43 Proteinopathy, Paragraph 2: BAlthough mostly nuclear, up to ~30 % of TDP-43 protein can be found in the cytoplasm [16], with nuclear efflux regulated by both activity and stress [17].^ Reference 17 should be: Wang IF, Wu LS, Chang HY, Shen CK. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem. 2008;105(3):797806. doi:10.1111/j.1471-4159.2007.05190.x. Protein degradation gene mutations, Paragraph 1: BTDP43 proteostasis is normally maintained by the coordinated action of the UPS and autophagy, which is particularly important for clearing TDP-43 oligomers and aggregates [81–87].^ This should be references 83-87 Protein degradation gene mutations, Paragraph 2: BNotably, VCP and p62 are required for the formation of Baggresomes^ [84, 88, 89], which are large perinuclear inclusions decorated with ubiquitin, ubiquilin, and p 62.^ Reference 84 should be: Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated prote in aggregates by autophagy. J Biol Chem. 2007;282(33):24131-45 (originally designated reference 79) Protein degradation gene mutations, Paragraph 2: BThe TDP43-positive aggregates that are the hallmark ALS pathology are likely aggresomes [76, 90].^ Reference 76 should be: Scotter EL, Vance C, Nishimura AL, et al. Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species. J Cell Sci 2014;127: 1263–1278. (originally designated reference 83) Protein degradation gene mutations, Paragraph 4: BCertainly, small molecule activators of the UPS or autophagy The online version of the original article can be found at http://dx.doi.org/ 10.1007/s13311-015-0338-x. E. L. Scotter :H.