Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both familial and idiopathic forms of Parkinson's disease (PD). Neuroinflammation is a key event in neurodegeneration and aging, and there is mounting evidence of LRRK2 involvement in inflammatory pathways. In a previous study, we described an alteration of the inflammatory response in dermal fibroblasts from PD patients expressing the G2019S and R1441G mutations in LRRK2. Methods: Taking advantage of cellular reprogramming, we generated induced pluripotent stem cell (iPSC) lines and neurons thereafter, harboring LRRK2G2019S and LRRK2R1441G mutations. We used gene silencing and functional reporter assays to characterize the effect of the mutations. We examined the temporal profile of TNF alpha-induced changes in proteins of the NF-kappa B pathway and optimized western blot analysis to capture alpha-synuclein dynamics. The effects of the mutations and interventions were analyzed by two-way ANOVA tests with respect to corresponding controls. Results: LRRK2 silencing decreased alpha-synuclein protein levels in mutated neurons and modified NF-kappa B transcriptional targets, such as PTGS2 (COX-2) and TNFAIP3 (A20). We next tested whether NF-kappa B and alpha-synuclein pathways converged and found that TNF alpha modulated alpha-synuclein levels, although we could not detect an effect of LRRK2 mutations, partly because of the individual variability. Nevertheless, we confirmed NF-kappa B dysregulation in mutated neurons, as shown by a protracted recovery of I kappa B alpha and a clear impairment in p65 nuclear translocation in the LRRK2 mutants. Conclusions: Altogether, our results show that LRRK2 mutations affect alpha-synuclein regulation and impair NF-kappa B canonical signaling in iPSC-derived neurons. TNFa modulated alpha-synuclein proteostasis but was not modified by the LRRK2 mutations in this paradigm. These results strengthen the link between LRRK2 and the innate immunity system underscoring the involvement of inflammatory pathways in the neurodegenerative process in PDThis study is funded by grants from the Spanish Ministry of Economy and Competitiveness (MINECO), Fondo de Investigaciones Sanitarias PI15/00486, the European Commission FP7 Health -278871, and the Joint Program in Neurodegenerative Diseases AC 14/0041 (DAMNDPATHS) to RSP

Hematoma de septo interauricular como complicación postquirúrgica inusual: A propósito de un caso

Atrial septal hematoma is a rare entity that can be caused by various etiologies. Mitral valve surgery is the most common iatrogenic cause of atrial septal hematoma or dissection, although it has also been described as a complication of other surgical and percutaneous procedures. We present a case of a woman with an interatrial septal hematoma as a post-surgical complication. Through this clinical case we will briefly review this rare entity.El hematoma del septo interauricular constituye una entidad poco habitual que puede tener diferentes etiologías. La cirugía sobre la válvula mitral es la causa iatrogénica de hematoma o disección de septo interauricular más frecuente, aunque también se ha descrito como complicación de otros procedimientos tanto quirúrgicos como percutáneos. Presentamos un caso de una mujer con un hematoma de septo interauricular como complicación postquirúrgica. A través de este caso clínico haremos una pequeña revisión de esta rara entidad