TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in ALS/FTD and related disorders.

Nuclear clearance and cytoplasmic aggregation of the RNA-binding protein TDP-43 are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and fronto- temporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet, this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from RNA-seq (DaPars) tool to ALS/FTD transcriptome datasets, and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional significance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3'UTRs, resulting in greater transcript stability and elevated MARK3 protein levels, which promotes increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously unrecognized feature of TDP-43-driven disease pathology in ALS/FTD and highlight a potentially novel mechanistic link between TDP-43 dysfunction and tau regulation.

Comparison of the iv and ip routes of administration of cisplatin in dogs.

Cisplatin at a dose of 3 mg/kg was administered to dogs either iv or ip. Cisplatin concentrations in serum, urine, and tissues were measured with a radioisotope tracer method employing 195mPt cisplatin. Systemic toxicity was monitored by serial BUN, creatinine, and wbc and platelet counts. The mode of administration did not affect systemic toxicity since the changes in renal and bone marrow functions were identical in the two groups. Serum cisplatin levels following iv administration peaked at 13.5 micrograms/ml at 5 minutes and were biphasic with rapid initial decline and a prolonged elimination phase. In contrast, levels following ip administration increased rapidly to 1.5 micrograms/ml at 4 hours and then decreased with the iv levels. The amount of drug recovered in the urine was similar regardless of method of administration, with approximately 50% of the injected dose excreted by Day 4. The drug levels within the tissues on Days 4 and 8 were similar, with the exception of the tissues lining the peritoneal cavity. On Day 4 the tissues lining the peritoneal cavity had 2.5-8 times higher levels of drug after ip administration, and this difference was statistically significant (P less than 0.01). Local toxic effects encountered with ip administration consisted of bloody ascites on Day 4 (four of none dogs) and filmy adhesions on Day 8 (one of four dogs). It is concluded that ip cisplatin chemotherapy may increase the therapeutic index for small tumors which are confined to the peritoneal cavity.