Mounting evidence of FKBP12 implication in neurodegeneration

Abstract

Intrinsically disordered proteins, such as tau or α-synuclein, have long been associated with a dysfunctional role in neurodegenerative diseases. In Alzheimer’s and Parkinson’s’ diseases, these proteins, sharing a common chemical-physical pattern with alternating hydrophobic and hydrophilic domains rich in prolines, abnormally aggregate in tangles in the brain leading to progressive loss of neurons. In this review, we present an overview linking the studies on the implication of the peptidyl-prolyl isomerase domain of immunophilins, and notably FKBP12, to a variety of neurodegenerative diseases, focusing on the molecular origin of such a role. The involvement of FKBP12 dysregulation in the aberrant aggregation of disordered proteins pinpoints this protein as a possible therapeutic target and, at the same time, as a predictive biomarker for early diagnosis in neurodegeneration, calling for the development of reliable, fast and cost-effective detection methods in body fluids for community-based screening campaigns.

Proteomic Analysis of Rhesus Macaque Brain Explants Treated With Borrelia burgdorferi Identifies Host GAP-43 as a Potential Factor Associated With Lyme Neuroborreliosis

“…Like many bioactive proteins, GAP‐43 is intrinsically disordered, lacking a stable tertiary and/or secondary structure under in vitro physiologic conditions ( Uversky, 2010 ; Forsova and Zakharov, 2016 ), the functional significance of this feature has not been thoroughly studied ( Chiti and Dobson, 2006 ). Nonetheless, many disordered proteins such as amyloid β-protein and tau protein are soluble or can form aggregates that have been linked to the pathogenesis of neurodegenerative diseases ( Caminati and Procacci, 2020 ). GAP-43 functions as an actin regulator and changes in its expression can lead to accumulation of the actin-depolymerising factor cofilin and the formation of cofilin–actin rods, which can impair synaptic function and cause the loss of synapses ( Chung et al., 2020 ).…”

Proteomic Analysis of Rhesus Macaque Brain Explants Infected With Borrelia Burgdorferi Identifies Host GAP-43 As A Potential Factor Associated With Lyme Neuroborreliosis

“…Like many bioactive proteins, GAP-43 is intrinsically disordered, lacking a stable tertiary and/or secondary structure under in vitro physiologic conditions [34,35], the functional signi cance of this feature has not been thoroughly studied [36]. Nonetheless, many disordered proteins such as amyloid β-protein and tau protein are soluble or can form aggregates that have been linked to the pathogenesis of neurodegenerative diseases [37]. GAP-43 functions as an actin regulator and changes in its expression can lead to accumulation of the actin-depolymerising factor co lin and the formation of co lin-actin rods, which can impair synaptic function and cause the loss of synapses [38].…”

Comprehensive Quantitative Proteome Analysis of Aedes aegypti Identifies Proteins and Pathways Involved in Wolbachia pipientis and Zika Virus Interference Phenomenon

“…The Wolbachia infection up-regulated 10 salivary gland proteins, such as endoplasmin (AAEL012827-PA), which is required for proper folding of Toll-like receptors in mammals (Fitzgerald and Kagan, 2020), and FKBP12 (AAEL010491-PB) that has a prolyl isomerase activity and bidins to immunosuppressive molecules (Caminati and Procacci, 2020).…”