Mechanism of neuronal death in familial encephalopathy with neuroserpin inclusion bodies (FENIB); Implications for mutant neuroserpin degradation – a study in mus musculus

Abstract

The inheritable dementia FENIB (familial encephalopathy with neuroserpin inclusion bodies) is caused by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum (ER) of neurons. Intracellular deposits of mutant neuroserpin challenge the fidelity of protein homeostasis, also proteostasis, which ensures a balanced interplay between protein synthesis, folding and clearance. Maintenance of cytosolic neuronal proteostasis is supported by the ubiquitin proteasome system (UPS) and the autophagy-lysosomal pathways. As mutant neuroserpin accumulates in the ER of neurons, we addressed how disturbance of ER proteostasis leads to neurodegeneration in a murine model of FENIB. Specifically, we studied the role of ER associated degradation (ERAD) and autophagy on mutant neuroserpin degradation in mice expressing mutant Tg(NSS49P) or wild-type Tg(NS) neuroserpin. We showed that mutant neuroserpin is specifically degraded by the proteasome via ERAD and non-specifically by autophagy. Only when the proteasomal activity is impaired, does autophagy contribute to mutant neuroserpin degradation. Further on, we studied the impact of the unfolded protein response (UPR) in regulating amounts of aggregated proteins. Transient induction of UPR in Tg(NSS49P) mice controls polymeric protein formation and aggregation in young mice. With increasing age, the capacity to mount UPR ceases and the amount of polymeric proteins and aggregates rises exponentially. Thus, our data support the concept of disturbed neuronal proteostasis in dementias and point towards age-related exhaustion of proteostasis maintaining mechanisms which are decisive for disease progression in dementias with intracellular protein depositions.