The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy.

TDP-43 is a soluble, nuclear protein that undergoes cytoplasmic redistribution and aggregation in the majority of cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 autoregulates the abundance of its own transcript TARDBP by binding to an intron in the 3 ′ untranslated region, although the mechanisms underlying this activity have been debated. Herein, we provide the most extensive analysis of TARDBP transcript yet undertaken. We detail the existence of a plethora of complex splicing events and alternative poly(A) use and provide data that explain the discrepancies reported to date regarding the autoregulatory capacity of TDP-43. Additionally, although many splice isoforms emanating from the TARDBP locus contain the regulated intron in the 3 ′ UTR, we find only evidence for autoregulation of the transcript encoding full-length TDP-43. Finally, we use a novel cytoplasmic isoform of TDP to induce disease-like loss of soluble, nuclear TDP-43, which results in aberrant splicing and up-regulation of endogenous TARDBP. These results reveal a previously underappreciated complexity to TDP-43 regulated splicing and suggest that loss of TDP-43 autoregulatory capacity may contribute to the pathogenesis of ALS.

OBJECTIVE The effect of obesity on outcomes in minimally invasive surgery (MIS) approaches to posterior lumbar surgery is not well characterized. The authors aimed to determine if there was a difference in operative variables and complication rates in obese patients who underwent MIS versus open approaches in posterior spinal surgery, as well as between obese and nonobese patients undergoing MIS approaches. METHODS A retrospective review of all consecutive patients who underwent posterior lumbar surgery from 2013 to 2016 at a single institution was performed. The primary outcome measure was postoperative complications. Secondary outcome measures included estimated blood loss (EBL), operative time, the need for revision, and hospital length of stay (LOS); readmission and disposition were also reviewed. Obese patients who underwent MIS were compared with those who underwent an open approach. Additionally, obese patients who underwent an MIS approach were compared with nonobese patients. Bivariate and multivariate analyses were carried out between the groups. RESULTS In total, 423 obese patients (57.0% decompression and 43.0% fusion) underwent posterior lumbar MIS. When compared with 229 obese patients (56.8% decompression and 43.2% fusion) who underwent an open approach, patients in both the obese and nonobese groups who underwent MIS experienced significantly decreased EBL, LOS, operative time, and surgical site infections (SSIs). Of the nonobese patients, 538 (58.4% decompression and 41.6% fusion) underwent MIS procedures. When compared with nonobese patients, obese patients who underwent MIS procedures had significantly increased LOS, EBL, operative time, revision rates, complications, and readmissions in the decompression group. In the fusion group, only LOS and disposition were significantly different. CONCLUSIONS Obese patients have poorer outcomes after posterior lumbar MIS when compared with nonobese patients. The use of an MIS technique can be of benefit, as it decreased EBL, operative time, LOS, and SSIs for posterior decompression with or without instrumented fusion in obese patients.

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