The Latest Articles on Amyloid Proteins and Ageing related Neurodegenerative Diseases
Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Amyloid Proteins and Ageing related Neurodegenerative Diseases.
Title: Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases
Authors: Rolf Antonie Loch, Hongzhi Wang, Alex Perálvarez-Marín, Philipp Berger, Henrietta Nielsen, Angeliki Chroni, Jinghui Luo
Type: Review
Abstract:
Three common Apolipoprotein E isoforms, ApoE2, ApoE3, and ApoE4, are key regulators of lipid homeostasis, among other functions. Apolipoprotein E can interact with amyloid proteins. The isoforms differ by one or two residues at positions 112 and 158, and possess distinct structural conformations and functions, leading to isoform-specific roles in amyloid-based neurodegenerative diseases. Over 30 different amyloid proteins have been found to share similar characteristics of structure and toxicity, suggesting a common interactome. The molecular and genetic interactions of ApoE with amyloid proteins have been extensively studied in neurodegenerative diseases, but have not yet been well connected and clarified. Here we summarize essential features of the interactions between ApoE and different amyloid proteins, identify gaps in the understanding of the interactome and propose the general interaction mechanism between ApoE isoforms and amyloid proteins. Perhaps more importantly, this review outlines what we can learn from the interactome of ApoE and amyloid proteins; that is the need to see both ApoE and amyloid proteins as a basis to understand neurodegenerative diseases.
Access this article: https://doi.org/10.1016/j.csbj.2023.01.022
Title: The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif
Authors: Carmela Matrone
Type: Mini Review
Abstract:
Neurodegenerative diseases are characterized by the progressive decline of neuronal function in several brain areas, and are always associated with cognitive, psychiatric, or motor deficits due to the atrophy of certain neuronal populations.
Most neurodegenerative diseases share common pathological mechanisms, such as neurotoxic protein misfolding, oxidative stress, and impairment of autophagy machinery.
Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset motor neuron disorders worldwide. It is clinically characterized by the selective and progressive loss of motor neurons in the motor cortex, brain stem, and spinal cord, ultimately leading to muscle atrophy and rapidly progressive paralysis.
Multiple recent studies have indicated that the amyloid precursor protein (APP) and its proteolytic fragments are not only drivers of Alzheimer’s disease (AD) but also one of the earliest signatures in ALS, preceding or anticipating neuromuscular junction instability and denervation. Indeed, altered levels of APP peptides have been found in the brain, muscles, skin, and cerebrospinal fluid of ALS patients.
In this short review, we discuss the nature and extent of research evidence on the role of APP peptides in ALS, focusing on the intracellular C-terminal peptide and its regulatory motif 682YENPTY687, with the overall aim of providing new frameworks and perspectives for intervention and identifying key questions for future investigations.
Access this article: https://doi.org/10.1016/j.csbj.2023.01.008
Title: Site-directed double monoubiquitination of the repeat domain of the amyloid-forming protein tau impairs self-assembly and coacervation
Authors: Daniele Trivellato, Fulvio Floriani, Carlo Giorgio Barracchia, Francesca Munari, Mariapina D'Onofrio, Michael Assfalg
Type: Research Article
Abstract:
In Alzheimer's disease and related disorders called tauopathies, the microtubule-associated protein tau accumulates in the brain in the form of amyloid-like supramolecular filaments. As an intrinsically disordered protein, tau undergoes many post-translational modifications, including ubiquitination. Alterations to the levels of ubiquitination of tau have been observed at various stages of neurodegenerative conditions.
We focus on proteoform-specific interrogations to obtain mechanistic insight into the effects of ubiquitination on disease-related conformational transitions of tau. Single and double ubiquitination of tau at residues Lys311 and Lys317 is strongly associated with pathological conditions. In this study, we leveraged disulfide-directed chemistry to install ubiquitin at one or both of those positions in the isolated microtubule-binding repeat domain of tau. We obtained homogeneously modified tau proteins and observed that they retained disordered character in solution.
We found that ubiquitination in position 317 (with or without ubiquitination in position 311) impaired the formation of ordered fibrillar structures via oligomeric intermediates. Since the transition to fibrillar species may proceed via an alternative condensation pathway involving liquid droplet intermediates, we further tested the ability of the ubiquitinated proteoforms to phase separate. Single monoubiquitinated tau species were able to coacervate, however no liquid droplets were observed for the double ubiquitinated form.
Taken together, the data indicate that double ubiquitination in the third repeat of tau disfavors the formation of amyloid aggregates by distinct mechanisms, suggesting that the presence of ubiquitinated residues 311 and 317 in insoluble tau may result from modifications in advanced stages of aggregation. These findings contribute to our understanding of the influence of site-specific ubiquitination on the pathological conformational transitions of a prototypical intrinsically disordered protein.
Access this article: https://doi.org/10.1016/j.bioorg.2023.106347
Title: Melatonin reduces β-amyloid accumulation and improves short-term memory in streptozotocin-induced sporadic Alzheimer's disease model
Authors: Marcos K Andrade, Leonardo C Souza, Evellyn M. Azevedo, Ellen L Bail, Silvio M Zanata, Roberto Andreatini, Maria A.B.F. Vital
Type: Research Article
Abstract:
Melatonin is a hormone secreted by the pineal gland, it can be associated with circadian rhythms, aging and neuroprotection. Melatonin levels are decreased in sporadic Alzheimer's disease (sAD) patients, which suggests a relationship between the melatonergic system and sAD. Melatonin may reduce inflammation, oxidative stress, TAU protein hyperphosphorylation, and the formation of β-amyloid (Aβ) aggregates. Therefore, the objective of this work was to investigate the impact of treatment with 10 mg/kg of melatonin (i.p) in the animal model of sAD induced by the intracerebroventricular (ICV) infusion of 3 mg/kg of streptozotocin (STZ). ICV-STZ causes changes in the brain of rats similar to those found in patients with sAD. These changes include; progressive memory decline, the formation of neurofibrillary tangles, senile plaques, disturbances in glucose metabolism, insulin resistance and even reactive astrogliosis characterized by the upregulation of glucose levels and glial fibrillary acidic protein (GFAP). The results show that ICV-STZ caused short-term spatial memory impairment in rats after 30 days of STZ infusion without locomotor impairment which was evaluated on day 27 post-injury. Furthermore, we observed that a prolonged 30-day treatment with melatonin can improve the cognitive impairment of animals in the Y-maze test, but not in the object location test. Finally, we demonstrated that animals receiving ICV-STZ have high levels of Aβ and GFAP in the hippocampus and that treatment with melatonin reduces Aβ levels but does not reduce GFAP levels, concluding that melatonin may be useful to control the progression of amyloid pathology in the brain.
Access this article: https://doi.org/10.1016/j.ibneur.2023.01.005
Title: Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury
Authors: Zhiping Mi, Steven H. Graham
Type: Review
Abstract:
UCHL1 is a multifunctional protein expressed at high concentrations in neurons in the brain and spinal cord. UCHL1 plays important roles in regulating the level of cellular free ubiquitin and redox state as well as the degradation of select proteins. This review focuses on the potential role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury and recovery. Subjects addressed in the review include 1) Normal physiological functions of UCHL1. 2) Posttranslational modification sites and splice variants that alter the function of UCHL1 and mouse models with mutations and deletions of UCHL1. 3) The hypothesized role and pathogenic mechanisms of UCHL1 in neurodegenerative diseases and brain injury. 4) Potential therapeutic strategies targeting UCHL1 in these disorders.
Access this article: https://doi.org/10.1016/j.arr.2023.101856
