The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.

Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.

Role of the Mosaic Cisternal Maturation Machinery in Glycan Synthesis and Oncogenesis.

Tumorigenesis is associated with the deregulation of multiple processes, among which the glycosylation of lipids and proteins is one of the most extensively affected. However, in most cases, it remains unclear whether aberrant glycosylation is a cause, a link in the pathogenetic chain, or a mere consequence of tumorigenesis. In other cases, instead, studies have shown that aberrant glycans can promote oncogenesis. To comprehend how aberrant glycans are generated it is necessary to clarify the underlying mechanisms of glycan synthesis at the Golgi apparatus, which are still poorly understood. Important factors that determine the glycosylation potential of the Golgi apparatus are the levels and intra-Golgi localization of the glycosylation enzymes. These factors are regulated by the process of cisternal maturation which transports the cargoes through the Golgi apparatus while retaining the glycosylation enzymes in the organelle. This mechanism has till now been considered a single, house-keeping and constitutive function. Instead, we here propose that it is a mosaic of pathways, each controlling specific set of functionally related glycosylation enzymes. This changes the conception of cisternal maturation from a constitutive to a highly regulated function. In this new light, we discuss potential new groups oncogenes among the cisternal maturation machinery that can contribute to aberrant glycosylation observed in cancer cells. Further, we also discuss the prospects of novel anticancer treatments targeting the intra-Golgi trafficking process, particularly the cisternal maturation mechanism, to control/inhibit the production of pro-tumorigenic glycans.

Permeability of gloves used in nuclear medicine departments to [(99m)Tc]-pertechnetate and [(18)F]-fluorodeoxyglucose: radiation protection considerations.

In order to evaluate the safety of the individual protection devices, the permeability of four different types of disposable gloves, commonly used in hospitals, was tested in relation to [(99m)Tc]-pertechnetate and to [(18)F]-fluorodeoxyglucose ([(18)F]-FDG). From these radiopharmaceutical solutions, a drop was deposited on the external surface of the glove which was opened and stretched with the external surface placed upward. The smear test technique permitted to evaluate the activity onto the inner surface of the glove at different times. The smear tests were measured in a well sodium iodide detector calibrated in efficiency for (99m)Tc and (18)F. The permeability was tested on ten samples of each type of gloves and was expressed as the ratio of the activity onto the inner surface at each time interval to the activity deposited on the external surface of the glove. For each type of gloves and for each sampling time, mean value, standard deviation and percentage coefficient of variation of permeability were evaluated. One type of gloves showed a low resistance to permeation of both radiopharmaceuticals, while another one only to pertechnetate. The other gloves were good performers. The results of this study suggest to test permeability for gloves used for handling radiopharmaceuticals, before their adoption in the clinical routine. This practice will provide a more careful service of radiation protection for nuclear medicine department staff.

[Description of a case of rheumatoid pleuropneumopathy with primary onset]. / Descrizione di un caso di pleuropneumopatia reumatoide ad insorgenza primitiva.

A case of pleuropulmonary manifestation as the first symptom of rheumatoid arthritis is reported; articular involvement followed at a later stage. Pleuropulmonary localisation of rheumatoid arthritis is varied and infrequent; it is seldom the first manifestation of illness. This case was particular because isolated pleuropulmonary symptom appeared in a subject negative rheumatoid factor. The patient improved after initial NSAIDS treatment, followed by corticosteroids and NSAIDS together, leading to the resolution of clinical and x-ray symptoms.