Interaction of RAGE with α-synuclein fibrils mediates inflammatory response of microglia

Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy

“…As key pathological entities in a variety of devastating neurodegenerative diseases, amyloid fibrils fulfill their pathological activities by interacting with a wide spectrum of proteins, including membrane receptors on neurons and microglia, chaperones, proteins from mitochondria, and autophagosome. , For example, α-syn fibril can promote neuroinflammation by interacting with microglial membrane proteins including Toll-Like Receptors and RAGE ,, and can also capture proteasome to impair protein homeostasis. , Thus, structural investigation of the interplay between amyloid fibrils and their binding proteins is important for the mechanistic understanding of amyloid pathologies. In this work, by combining INEPT-based ssNMR and cryo-EM, we characterized the interaction between α-syn fibril and L3D1.…”

“…Abnormal amyloid aggregation of a variety of proteins, such as amyloid-β (Aβ), Tau, α-synuclein (α-syn), and TDP-43 is closely associated with the initiation and progression of different neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). 1−3 Mounting evidence has shown that amyloid fibrils serve as the key pathological entities with a wide range of distinct pathological activities, including neuron-toneuron transmission and propagation, 4,5 disruption of protein quality control, 6,7 induction of neuroinflammation, 8 and cell death. 9,10 Over the past two decades, structures of different amyloid fibrils have been intensively investigated by solid-state NMR (ssNMR) and cryo-electron microscopy (cryo-EM).…”

“…For example, in the structure of α-syn fibril polymorph 1a, residues V37-Q99 form the rigid FC, while the residues of N- and C-TRs are disordered and invisible for either cryo-EM or CP-based ssNMR. , However, the TRs of α-syn have been found to play an essential role in mediating α-syn fibril pathology. For example, C-TR has been reported to bind with various receptors including LAG3, APLP1, and RAGE, which mediates neuron-to-neuron transmission and neuroinflammation of pathological α-syn fibrils in diseased brains. ,− It has also been reported that Hsp70 and its co-chaperones disaggregate fibrils by Hsp40 binding to the C-TR and Hsp70 binding to N-TR of α-syn fibril . Therefore, the structural basis underlying the interplay between fibrils and the binding proteins is of great importance yet poorly understood.…”

“…Abnormal amyloid aggregation of a variety of proteins, such as amyloid-β (Aβ), Tau, α-synuclein (α-syn), and TDP-43 is closely associated with the initiation and progression of different neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). − Mounting evidence has shown that amyloid fibrils serve as the key pathological entities with a wide range of distinct pathological activities, including neuron-to-neuron transmission and propagation, , disruption of protein quality control, , induction of neuroinflammation, and cell death. , Over the past two decades, structures of different amyloid fibrils have been intensively investigated by solid-state NMR (ssNMR) and cryo-electron microscopy (cryo-EM). − Most amyloid proteins employ a portion of their sequences to form a rigid fibril core (FC), while leaving the rest, usually terminal sequences (referred to as terminal regions, TRs) disordered and coating on the surface of the FC . Many studies have shown that the FC represents the polymorphic structures and the overall physiochemical properties of the fibrils, including stability, stiffness, and seeding capability. ,, In contrast, the TRs play an important role in mediating the interaction between amyloid fibril and different binding proteins, including receptors, − chaperones, − and proteasome, to fulfill various pathological activities.…”

RAGE Inhibitors in Neurodegenerative Diseases

“…The AGE-crosslinked proteins would lead to various pathological effects, depending on the location of the AGEs. For example, the AGE-modified amyloid-β peptides (Aβ 1–42 , Aβ 1–40 ) are abundant in the intercellular spaces of neuronal cells and they ultimately are the causative factors in neuronal disintegration and thereby the onset of neurodegenerative diseases, including AD, Parkinson’s disease and ALS [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. Furthermore, the AGEs are abundantly formed in the vascular tissue of diabetic and atherosclerosis cases [ 38 , 39 , 40 ].…”