Neuroprotective role of the ER co-chaperone SIL1 in human neurodegenerative disease


Abnormal accumulations of misfolded proteins that elicit endoplasmic reticulum (ER) stress are major pathological hallmarks of neurodegenerative disease such as Alzheimer´s disease, Parkinson´s disease, and Amyotrophic lateral sclerosis (ALS). Mutations in the ER co-chaperon SIL1 cause Marinesco-Sjögren-Syndrome, which is characterized clinically by cerebellar degeneration, cataracts, and vacuolar myopathy. Research teams from Aachen, Munich, Amsterdam and Bern recently reported in joint publications that SIL1 mutation leads to peculiar ER alterations in patients and mice and that SIL1 regulates motor neuron subtype-selective ER stress in ALS. Results obtained with G93A-SOD1 transgenic ALS mice suggest that SIL1 protects neurons from ER stress and ER stress induced autophagy. These findings suggest that SIL1 could be a therapeutic target in motor neuron diseases and other neurodegenerative disorders.

Filézac de L’Etang A, Maharjan N, Cordeiro Braña M, Ruegsegger C, Rehmann R, Goswami A, Roos A, Troost D, Schneider BL, Weis J, Saxena S. Marinesco-Sjögren syndrome protein SIL1 contributes to motoneuron subtype-selective ER stress and degeneration in fALS mice. Nature Neurosci. 2015 Feb;18(2):227-38. Roos A, Buchkremer S, Kollipara L, Labisch T, Gatz C, Zitzelsberger M, Brauers E, Nolte K, Schröder JM, Kirschner J, Jesse CM, Goebel HH, Goswami A, Zimmermann R, Zahedi RP, Senderek J, Weis J. Myopathy in Marinesco-Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology. Acta Neuropathol. 2014 May;127(5):761-77.

Krieger M, Roos A, Stendel C, Claeys KG, Sonmez FM, Baudis M, Bauer P, Bornemann  A, de Goede C, Dufke A, Finkel RS, Goebel HH, Häussler M, Kingston H, Kirschner J, Medne L, Muschke P, Rivier F, Rudnik-Schöneborn S, Spengler S, Inzana F, Stanzial F, Benedicenti F, Synofzik M, Lia Taratuto A, Pirra L, Tay SK, Topaloglu H, Uyanik G, Wand D, Williams D, Zerres K, Weis J, Senderek J. SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome. Brain. 136(Pt 12): 3634-44, 2013