The emerging role of furin in neurodegenerative and neuropsychiatric diseases

Abstract

Furin is an important mammalian proprotein convertase that catalyzes the proteolytic maturation of a variety of prohormones and proproteins in the secretory pathway. In the brain, the substrates of furin include the proproteins of growth factors, receptors and enzymes. Emerging evidence, such as reduced FURIN mRNA expression in the brains of Alzheimer’s disease patients or schizophrenia patients, has implicated a crucial role of furin in the pathophysiology of neurodegenerative and neuropsychiatric diseases. Currently, compared to cancer and infectious diseases, the aberrant expression of furin and its pharmaceutical potentials in neurological diseases remain poorly understood. In this article, we provide an overview on the physiological roles of furin and its substrates in the brain, summarize the deregulation of furin expression and its effects in neurodegenerative and neuropsychiatric disorders, and discuss the implications and current approaches that target furin for therapeutic interventions. This review may expedite future studies to clarify the molecular mechanisms of furin deregulation and involvement in the pathogenesis of neurodegenerative and neuropsychiatric diseases, and to develop new diagnosis and treatment strategies for these diseases.

Estrogen Receptor Genes, Cognitive Decline, and Alzheimer Disease

“…The 4 genes were ZC3H11A , FURIN , SMARCD3 , and PPP4R2 , and 2 of them were previously reported associated with gray matter volume ( ZC3H11A ) 37 and AD ( FURIN ). 38 These sensitivity analyses supported the association of GPER1 RNA expression in DLPFC with AD phenotypes in women.…”

“…The analyses indicated that 4 genes had the same type of associations that GPER1 had: their RNA expressions were associated with faster cognitive decline and more tau tangles. The 4 genes were ZC3H11A, FURIN, SMARCD3, and PPP4R2, and 2 of them were previously reported associated with gray matter volume (ZC3H11A) 37 and AD (FURIN) 38 . These sensitivity analyses supported the association of GPER1 RNA expression in DLPFC with AD phenotypes in women…”

Permethrin as a Potential Furin Inhibitor through a Novel Non-Competitive Allosteric Inhibition

“…Most of the existing furin inhibitors were developed based on furin-substrate peptide analogs, which have good binding to the catalytic pocket of furin but lack chemical and structural diversity [ 18 , 37 ]. Additionally, given the importance of furin in multiple diseases including SARS-CoV-2 infection and tumors, its biochemical studies need to be more advanced [ 7 , 8 , 38 , 39 ]. In the present work, a potential inhibitor of furin with a novel backbone was identified, more importantly, its novel non-competitive allosteric regulatory mode was discovered through enzyme kinetic experiments and structural simulation studies.…”

“…Furin is associated with a variety of diseases, such as cardiovascular diseases and endocrine system disorders, and is especially closely related to viral infections and tumors [ 5 , 6 , 7 , 8 ]. With the outbreak of COVID-19 in the last three years, research related to furin-mediated viral infections has been accelerated.…”

Ferroptosis, Pyroptosis, and Cuproptosis in Alzheimer’s Disease

“…When the total iron content is excessive, the activity of furin decreases, and the activity of β-secretase increases, which enhances the production of the amyloid pathway. In contrast, when iron was deficient, furin activity increased, α-secretase activity increased, and nonamyloid pathway formation was obvious …”