K63-linked ubiquitylation induces global sequestration of mitochondria.

Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. To address this question, we have engineered the ubiquitin ligase ProxE3, which in an inducible manner synthesizes K63-linked ubiquitin chains on the surface of mitochondria. We found that the presence of K63-linked ubiquitin chains on mitochondria resulted in the recruitment of the ubiquitin adaptor p62 and induced a dramatic redistribution of mitochondria, which was reminiscent to the Parkin-facilitated sequestration in response to mitochondrial uncoupler. However, ProxE3 did not induce autophagic degradation of mitochondria. Our data show that K63-linked ubiquitin chains at the mitochondrial membrane are sufficient for the induction of mitochondrial sequestration, but not mitophagy, without the need of extrinsically inflicting mitochondrial dysfunction.

Expression of progerin in aging mouse brains reveals structural nuclear abnormalities without detectible significant alterations in gene expression, hippocampal stem cells or behavior.

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental progeroid syndrome with multiple features suggestive of premature accelerated aging. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. However, despite ubiquitous expression of lamin A in all differentiated cells, the HGPS mutation results in organ-specific defects. For example, bone and skin are strongly affected by HGPS, while the brain appears to be unaffected. There are no definite explanations as to the variable sensitivity to progeria disease among different organs. In addition, low levels of progerin have also been found in several tissues from normal individuals, but it is not clear if low levels of progerin contribute to the aging of the brain. In an attempt to clarify the origin of this phenomenon, we have developed an inducible transgenic mouse model with expression of the most common HGPS mutation in brain, skin, bone and heart to investigate how the mutation affects these organs. Ultrastructural analysis of neuronal nuclei after 70 weeks of expression of the LMNA c.1824C>T mutation showed severe distortion with multiple lobulations and irregular extensions. Despite severe distortions in the nuclei of hippocampal neurons of HGPS animals, there were only negligible changes in gene expression after 63 weeks of transgenic expression. Behavioral analysis and neurogenesis assays, following long-term expression of the HGPS mutation, did not reveal significant pathology. Our results suggest that certain tissues are protected from functional deleterious effects of progerin.

[Unusual disclosure of giant Meckel's diverticulum]. / Révélation inhabituelle d'un diverticule géant de Meckel.

At discovery of diabetes mellitus, complementary explorations revealed a superinfection of a giant Meckel's diverticulum. We present this clinical situation in one case and suggest possible nosologies. The epidemiology and clinical approach to Meckel's diverticulum are discussed.

[Spontaneous disappearance of herniation pit on the femoral neck]. / Disparition spontanée d'une lacune sous-corticale du col fémoral.

The authors present a case of a 39 years old patient who had a herniation pit of the left femoral neck, 5 years ago. This lesion disappeared spontaneously. To our knowledge, no report of healing of a herniation pit has been previously described.

[Primary malignant fibrous histiocytoma of the lung]. / Histiocytome fibreux malin primitif du poumon.

On the basis of one personal case, the various clinicopathological features of primary malignant fibrous histiocytoma of the lung are summed up. This tumor, which has a nonspecific radiological appearance, most often appears as a large peripheral pulmonary opacity, for which the prognosis is guarded and the positive diagnosis based on surgical exeresis or biopsy.