PERK inhibition delays neurodegeneration and improves motor function in a mouse model of Marinesco-Sjögren syndrome

Abstract

Marinesco-Sjögren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide exchange factor for the molecular chaperone BiP which is essential for correct protein folding in the endoplasmic reticulum. Woozy mice carrying a spontaneous Sil1 mutation recapitulate key pathological features of MSS, including cerebellar atrophy with degeneration of Purkinje cells and progressive myopathy. Because the PERK branch of the unfolded protein response is activated in degenerating neurons of woozy mice, and inhibiting PERK-mediated translational attenuation has shown protective effects in protein-misfolding neurodegenerative disease models, we tested the therapeutic efficacy of GSK2606414, a potent inhibitor of PERK. Mice were chronically treated with GSK2606414 starting from a presymptomatic stage, and the effects were evaluated on biochemical, histopathological and clinical readouts. GSK2606414 delayed Purkinje cell degeneration and the onset of motor deficits, prolonging the asymptomatic phase of the disease; it also reduced the skeletal muscle abnormalities and improved motor performance during the symptomatic phase. The protein but not the mRNA level of ORP150, a nucleotide exchange factor which can substitute for SIL1, was increased in the cerebellum of GSK2606414-treated woozy mice, suggesting that translational recovery promoted the synthesis of this alternative BiP co-factor. Targeting PERK signaling may have beneficial disease-modifying effects in carriers of SIL1 mutations.

Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration

“…The pathogenic role of dysregulated PERK-eIF2a-P signaling in neurons has been well characterized across the spectrum of neurodegenerative disorders (Grande et al, 2018;Halliday et al, 2015Halliday et al, , 2017Hoozemans et al, 2005Hoozemans et al, , 2007Kim et al, 2014;Mercado et al, 2018;Moreno et al, , 2013Radford et al, 2015;Stutzbach et al, 2013). PERK-P has been detected in astrocytes from human tauopathy diseases (Nijholt et al, 2012), but the pathogenic effect of astrocytic PERK signaling, if any, in these disorders is unknown.…”

“…In several mouse models of neurodegeneration, chronic PERK-eIF2a-P signaling results in the sustained reduction in global protein synthesis rates, leading to synaptic failure and neuronal loss Radford et al, 2015). Restoration of translation rates in neurons through genetic or pharmacological modulation of PERK-eIF2a-P signaling restores memory and synapse function (Costa-Mattioli et al, 2007;Ma et al, 2013;Sidrauski et al, 2013) and is profoundly neuroprotective in these models (Celardo et al, 2016;Grande et al, 2018;Halliday et al, 2015Halliday et al, , 2017Kim et al, 2014;Mercado et al, 2018;Moreno et al, , 2013Radford et al, 2015). The pathway has become an area of intense interest for the treatment of human neurodegenerative disorders, where increased levels of PERK-P and eIF2a-P occur in association with misfolded protein accumulation in Alzheimer's and Parkinson's diseases and related disorders (Hoozemans et al, 2005(Hoozemans et al, , 2007(Hoozemans et al, , 2009Smith and Mallucci, 2016;Stutzbach et al, 2013).…”

Review: Protein misfolding diseases – the rare case of Marinesco‐Sjögren syndrome

“…Consistent with UPR activation, CHOP and total and spliced XBP‐1 mRNAs are increased in the cerebellum of woozy mice . Increased BiP, phospho (P)‐eIF2α and CHOP are detectable by immunofluorescence in vulnerable PCs, with P‐eIF2α and CHOP up‐regulated starting from a pre‐degenerative stage (Table ) .…”

“…Woozy mice phenocopy key pathological features of MSS, including cerebellar atrophy and myopathy. The cerebellum develops normally, but at approximately 2 months of age Purkinje cells (PCs) of neocerebellar lobules I–VIII start to degenerate and by 4 months are almost completely lost, while PCs of part of lobule IX and lobule X of the vestibule‐cerebellum are spared (Table ) . Immunofluorescence analysis detects terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)‐positive nuclear staining and caspase‐3 activation indicative of apoptosis.…”

“…Like MSS patients, woozy and Sil1 Gt mice develop severe myopathy and muscle atrophy . Early signs of muscle disease, including non‐subsarcolemmal nuclei and autophagic vacuoles (Table ), can be seen in woozy mice already at 16 weeks of age, while severe myopathy develops later . Muscle cells also present alterations of the Golgi structure, swollen mitochondria, proliferated sarcoplasmic reticulum and chromatin condensation.…”