The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of α-synuclein (α-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed α-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the α-syn variants that form oligomers (i.e., E57K and E35K), whereas the α-syn variants that form fibrils very quickly are less toxic. We show that α-syn oligomers are toxic in vivo and that α-syn oligomers might interact with and potentially disrupt membranes. P arkinson disease (PD) is the most common movement disorder, currently affecting approximately 2% of the population older than age 60 y. Prominent neuropathological hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain (1) and the presence of α-syn-containing intracellular inclusions: Lewy bodies (LBs) and Lewy neurites (2). α-Syn, a 140-aa protein physiologically found in presynaptic terminals of neurons, is the major fibrillar protein in LBs and Lewy neurites in sporadic and inherited PD. Moreover, point mutations (A53T, A30P, E46K) and gene multiplications of human WT (hWT) α-syn are related to rare familial autosomal-dominant forms of early-onset PD (3-6), suggesting that increased gene dosage and aberrant protein structure may accelerate disease onset and progression.Recent reports indicate that the accumulation of α-syn can result in the formation of intermediate-state oligomers, and oligomers of different shapes and sizes have been described (7-10). These oligomers interact with lipids, disrupt membranes (7,8), and cause cell death in vitro (10, 11) and in nonmammalian models, such as Caenorhabditis elegans and Drosophila melanogaster (12). However, we are aware of no previous direct in vivo demonstration of the toxicity of α-syn oligomers in mammals.We aim to establish a model that allows specific testing of the effects of α-syn oligomerization in vitro and in vivo. To elucidate the causal structure-toxicity relationship of these oligomeric protein assemblies in a mammalian system, we designed "conformation-trapped" mutants based on structural modeling of α-syn fibrils (13, 14). Structurally, amyloid fibrils of α-syn are composed of cross-β-sheets (15). Residues from approximately 30 to 110 of α-syn form the core of the fibrils, whereas the approximately 30 N-terminal residues are heterogeneous and the approximately 30 C-terminal residues are flexible (13,14,16,17). Based on our structural model, recently developed from NMR data, the core of α-syn fibrils comprises five β-strands reminiscent of a five-layered "β-sandwich" (14). Several loops adjacent to and between the strands ar...
The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of ␣-synuclein (␣-syn) from monomers by intermediates into amyloid fibrils is the toxic diseasecausative mechanism. Here, we studied the structure of ␣-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five -strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30 -110 confirmed the presence of -sheet secondary structure. The data suggest that 1-strand interacts with 2, 2 with 3, 3 with 4, and 4 with 5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of Ϸ2 ؋ 3.5 nm. Based on the combination of these data and published structural studies, a fold of ␣-syn in the fibrils is proposed and discussed.amyloid ͉ NMR ͉ Parkinson's disease ͉ structure ͉ aggregation
SUMMARY Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Recent structural studies have shown that neurotrophins interact with dimers of the p75 neurotrophin receptor (p75NTR), but the actual mechanism of receptor activation has remained elusive. Here we show that p75NTR forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys257 in its transmembrane domain. Mutation of Cys257 abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75NTR/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75NTR. FRET experiments revealed a close association of p75NTR intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys257 did not alter the oligomeric state of p75NTR, the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75NTR by a novel mechanism involving rearrangement of disulphide-linked receptor subunits.
The subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus are the two main regions of the adult mammalian brain in which neurogenesis is maintained throughout life. Because alterations in adult neurogenesis appear to be a common hallmark of different neurodegenerative diseases, understanding the molecular mechanisms controlling adult neurogenesis is a focus of active research. Neurotrophic factors are a family of molecules that play critical roles in the survival and differentiation of neurons during development and in the control of neural plasticity in the adult. Several neurotrophins and neurotrophin receptors have been implicated in the regulation of adult neurogenesis at different levels. Here, we review the current understanding of neurotrophin modulation of adult neurogenesis in both the SVZ and SGZ. We compile data supporting a variety of roles for neurotrophins/neurotrophin receptors in different scenarios, including both expected and unexpected functions.
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