7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2-3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2-3-d)pyrimidin-4-amine and Nerve-Degeneration

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.

Topics: Adenine; Animals; Cerebellum; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Guanine Nucleotide Exchange Factors; Heterozygote; HSP70 Heat-Shock Proteins; Humans; Indoles; Loss of Function Mutation; Mice; Motor Activity; Nerve Degeneration; Protein Folding; Purkinje Cells; Spinocerebellar Degenerations; Unfolded Protein Response

Targeting stress-induced kinases that regulate protein synthesis may be a new therapeutic strategy for treating neurodegenerative diseases.

Topics: Adenine; Alzheimer Disease; Animals; eIF-2 Kinase; Female; Humans; Indoles; Male; Memory Disorders; Nerve Degeneration; Neuronal Plasticity; Prion Diseases; Unfolded Protein Response

During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.

Topics: Adenine; Administration, Oral; Animals; Blood-Brain Barrier; Brain; eIF-2 Kinase; Eukaryotic Initiation Factor-2; Indoles; Mice; Nerve Degeneration; Neuroprotective Agents; Phosphorylation; Prion Diseases; Prions; Protein Biosynthesis; Synapses; Unfolded Protein Response

Topics: Adenine; Animals; Indoles; Nerve Degeneration; Prion Diseases; Unfolded Protein Response