Periphilin is a novel interactor of synphilin-1, a protein implicated in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein and its interactor synphilin-1 are major components of these inclusions. Rare mutations in the alpha-synuclein and synphilin-1 genes have been implicated in the pathogenesis of PD; however, the normal function of these proteins is far from being completely elucidated. We, thus, searched for novel synphilin-1-interacting proteins and deciphered periphilin as new interactor. Periphilin isoforms are involved in multiple cellular functions in vivo, and the protein is broadly expressed during embryogenesis and in the adult brain. We show that periphilin displays an overlapping expression pattern with synphilin-1 in cellular and animal models and in Lewy bodies of PD patients. Functional studies demonstrate that periphilin, as previously shown for synphilin-1, displays an antiapoptotic function by reducing caspase-3 activity. Searching for mutations in the periphilin gene, we detected a K69E substitution in two patients of a PD family. Taken together, these findings support for the first time an involvement of periphilin in PD.

Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice.

Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death.

The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein--implications for Parkinson's disease.

Synphilin-1 is linked to Parkinson's disease (PD), based on its role as an alpha-synuclein (PARK1)-interacting protein and substrate of the ubiquitin E3 ligase Parkin (PARK2) and because of its presence in Lewy bodies (LB) in brains of PD patients. We found that overexpression of synphilin-1 in cells leads to the formation of ubiquitinated cytoplasmic inclusions supporting a derangement of the ubiquitin-proteasome system in PD. We report here a novel specific interaction of synphilin-1 with the regulatory proteasomal protein S6 ATPase (tbp7). Functional characterization of this interaction on a cellular level revealed colocalization of S6 and synphilin-1 in aggresome-like intracytoplasmic inclusions. Overexpression of synphilin-1 and S6 in cells caused reduced proteasomal activity associated with a significant increase in inclusion formation compared to cells expressing synphilin-1 alone. Steady-state levels of synphilin-1 in cells were not altered after cotransfection of S6 and colocalization of synphilin-1-positive inclusions with lysosomal markers suggests the presence of an alternative lysosomal degradation pathway. Subsequent immunohistochemical studies in brains of PD patients identified S6 ATPase as a component of LB. This is the first study investigating the physiological role of synphilin-1 in the ubiquitin proteasome system. Our data suggest a direct interaction of synphilin-1 with the regulatory complex of the proteasome modulating proteasomal function.

Comparison of two hospitalization modes in geriatrics either directly via a hotline or after an emergency unit admission.

Hospitalizations via the emergency services of the elderly represent on average 41% of the stays. The family physician is aware of the deleterious effects of using emergency rooms and know that intensive use contributes to the disorganization of these services. The provision of a telephone line, enabling doctors to have direct access to a geriatrician doctor, is a new service allowing, if necessary, direct hospitalization in geriatrics but its interest is still poorly evaluated. METHODS: From June 1st, 2015, to June 1st, 2016, we compared the route of care for inpatients directly in short stays of geriatrics thanks to the hotline (group hotline) versus the route of those passed by emergencies (group EU, emergency unit). RESULTS: 520 patients were included in the study. The duration of stay was shorter during hospitalization via the hotline, 11.6 [95% CI, 10.8-12.3] days in a direct hospitalization versus 14.1 [95% CI, 13.5-14.7] days of a passage through emergencies (p <0.05). Patients who were admitted to the emergency room were more likely to be hospitalized again. Among the 170 patients re-hospitalized, an average duration before re-hospitalization of 29.5 [CI 95%, 23.6-35.4] days was observed in patients hospitalised via the hotline, while those entered by emergencies were hospitalized in 24.1 [95% CI, 20.4-27.8] days (p <0.05). CONCLUSION: This analysis suggests that the intra-hospital course of geriatric patients directly addressed in short stays of geriatrics by direct admission was shorter and more efficient than the course of an intermediate stage in the emergencies. It seems important to discuss the generalization of the hotline device for the functioning of the geriatric pathway.

Should the Emergency Department be society's health safety net?

In the US health care system, a core safety net provider has two defining characteristics: (1) either by legal mandate or explicitly adopted mission, they maintain an "open door," offering patients services regardless of their ability to pay; and (2) a substantial portion of their patients are uninsured, on Medicaid, and/or otherwise vulnerable. The hospital Emergency Department (ED), by all accounts, falls within the definition of a core safety net provider. Yet many would argue that this is a primary health care role for which the ED was not originally intended or equipped. Should the ED be society's health-care safety net? Should it be the main provider of care for the indigent? Is this placing an unbearable strain on the ED? Should it be providing primary health-care? If not, what are the alternatives?