Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB

Abstract

Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded protein response. We use both cell lines and Drosophila models to show that the G392E mutant of neuroserpin that forms polymers is degraded by UBE2j1 E2 ligase and Hrd1 E3 ligase while truncated neuroserpin, a protein that lacks 132 amino acids, is degraded by UBE2g2 (E2) and gp78 (E3) ligases. The degradation of G392E neuroserpin results from SREBP-dependent activation of the cholesterol biosynthetic pathway in cells that express polymers of neuroserpin (G392E). Inhibition of HMGCoA reductase, the limiting enzyme of the cholesterol biosynthetic pathway, reduced the ubiquitination of G392E neuroserpin in our cell lines and increased the retention of neuroserpin polymers in both HeLa cells and primary neurones. Our data reveal a reciprocal relationship between cholesterol biosynthesis and the clearance of mutant neuroserpin. This represents the first description of a link between sterol metabolism and modulation of the proteotoxicity mediated by the EOR.

Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains

“…For instance, mutations in the neuroserpin protein cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) (Roussel et al . ). Miranda et al .…”

“…Interestingly, several neurodegenerative disorders are associated with misfolded proteins. For instance, mutations in the neuroserpin protein cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) (Roussel et al 2013). Miranda et al found a correlation with the severity of the symptoms (phenotype), the accumulation of the polymers and the type of mutation in a fly model and that a mutant that induces rapid protein polymerization causes an early-onset disease (Miranda et al 2008).…”

The endoplasmic reticulum remains functionally connected by vesicular transport after its fragmentation in cells expressing Z‐α1‐antitrypsin

“…It is feasible that interinclusion ER chaperone exchange may act to minimize ER heterogeneity, thereby protecting inclusion‐containing cells from ER stress. Further studies are required to test this directly, and also to establish whether the phenomenon described herein is generalizable to other circumstances of ER fragmentation‐for example, in Russell body–expressing plasma cells seen in chronic inflammation and multiple myeloma (38, 39), other serpinopathies such as FENIB (familial encephalopathy with neuroserpin inclusion bodies) (40), and in response to ischemia (41).…”

Interactions between N‐linked glycosylation and polymerisation of neuroserpin within the endoplasmic reticulum

“…The rate of polymerisation correlates with the phenotype observed in FENIB patients, with faster polymerisation being associated with earlier onset of disease [8,9]. Mutant NS is partially degraded by rapid ER associated degradation (ERAD), suggesting that it is targeted for degradation shortly after synthesis, but can also become trapped within long-lived polymers [8,[10][11][12][13].…”