Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.

Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjögren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.

The Role of the European Imperial Powers throughout the Armenian Schism in the 1870s

The Bull "Reversurus" (1867) and its dogmatic legitimization at the First Vatican Council in 1870 caused not only ecclesiastical controversy and Schism in the Armenian Catholic Church, but it had also wide political consequences for the Armenian Catholics in the Ottoman Empire. The conflict originally between the Armenian Catholics and Rome attracted very soon the attention of the European imperial Powers. France, the British Empire, the German Empire, Austria-Hungary and Russia were the main political powers who were involved in the Armenian affair. A full picture of the role of all these powers for the course of the Armenian Schism is missing. Mostly the role of France is foregrounded in the printed sources, as the main power, which supported the papacy to win during the Armenian affair. The role and the motives of the other imperial powers is almost missing. This article will try to describe as completely as possible the historical and political background, which brought to the escalation of the Armenian conflict beyond the national frontiers and led to number of conflicts at the international and transnational level. It will be shown that the imperial policy in Europe in the 19th century have played an enormous role throughout the Armenian Schism. It will be explained that several historical circumstances in Europe, especially the relation of the European imperial powers to each other as well as their expectations from the Ottoman Empire and its Armenian subjects were decisive for the duration and conclusion of the Armenian Schism.