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FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP –Pathology.

Authors :
Guettsches, Anne-Katrin
Meyer, Nancy
Zahedi, René P.
Evangelista, Teresinha
Muentefering, Thomas
Ruck, Tobias
Lacene, Emmanuelle
Heute, Christoph
Gonczarowska-Jorge, Humberto
Schoser, Benedikt
Krause, Sabine
Hentschel, Andreas
Vorgerd, Matthias
Roos, Andreas
Source :
Biomedicines; Oct2022, Vol. 10 Issue 10, pN.PAG-N.PAG, 18p
Publication Year :
2022

Abstract

Dominant VCP–mutations cause a variety of neurological manifestations including inclusion body myopathy with early–onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin–dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP–patients. Studying the proteomic signature of VCP–mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP–patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP–patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro–survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
22279059
Volume :
10
Issue :
10
Database :
Complementary Index
Journal :
Biomedicines
Publication Type :
Academic Journal
Accession number :
159870524
Full Text :
https://doi.org/10.3390/biomedicines10102443