Karyopherin abnormalities in neurodegenerative proteinopathies.
TL;DR: In this paper, the authors identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies.
Abstract: Neurodegenerative proteinopathies are characterised by progressive cell loss that is preceded by the mislocalisation and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, alpha-synuclein, Tar DNA binding protein-43, Fused in sarcoma and mutant Huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalised aggregates that characterise the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalisation and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalisation and aggregation of karyopherin alpha and beta proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalisation and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.
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TL;DR: In this article, the effects of various polyphenols in cell line and animal models of ALS/FTD are discussed, and possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.
Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, including mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed.
18 citations
TL;DR: Cargo leakage out of the nucleus is prevented by an enrichment of different soluble receptors, termed “karyopherins,” that are able to compensate for one another to reinforce the nuclear pore complex barrier in vivo.
Abstract: Kalita et al. show that cargo leakage out of the nucleus is prevented by an enrichment of different soluble receptors, termed “karyopherins,” that are able to compensate for one another to reinforce the nuclear pore complex barrier in vivo.
11 citations
TL;DR: In this paper, the authors discuss strategies to enhance NIR activity or expression, which could have therapeutic utility for several neurodegenerative disorders, including ALS, FTD, multisystem proteinopathy, limbic-predominant age-related TDP-43 encephalopathy, tauopathies, and related diseases.
9 citations
TL;DR: Kapβ proteins are well-known for their roles in facilitating nucleocytoplasmic transport and are also powerful chaperones, able to prevent and reverse aberrant material states of disease-relevant proteins, including those implicated in neurodegenerative disease as mentioned in this paper .
9 citations
TL;DR: In this article , a synthetic human α-Syn fibril strain was found to be uniquely capable of seeding α-synuclein fibrillization inside the nuclear compartment.
Abstract: The distinct neuropathological features of the different α-Synucleinopathies, as well as the diversity of the α-Synuclein (α-Syn) intracellular inclusion bodies observed in post mortem brain sections, are thought to reflect the strain diversity characterizing invasive α-Syn amyloids. However, this “one strain, one disease” view is still hypothetical, and to date, a possible disease-specific contribution of non-amyloid factors has not been ruled out. In Multiple System Atrophy (MSA), the buildup of α-Syn inclusions in oligodendrocytes seems to result from the terminal storage of α-Syn amyloid aggregates first pre-assembled in neurons. This assembly occurs at the level of neuronal cytoplasmic inclusions, and even earlier, within neuronal intranuclear inclusions (NIIs). Intriguingly, α-Syn NIIs are never observed in α-Synucleinopathies other than MSA, suggesting that these inclusions originate (i) from the unique molecular properties of the α-Syn fibril strains encountered in this disease, or alternatively, (ii) from other factors specifically dysregulated in MSA and driving the intranuclear fibrillization of α-Syn. We report the isolation and structural characterization of a synthetic human α-Syn fibril strain uniquely capable of seeding α-Syn fibrillization inside the nuclear compartment. In primary mouse cortical neurons, this strain provokes the buildup of NIIs with a remarkable morphology reminiscent of cat’s eye marbles (see video abstract). These α-Syn inclusions form giant patterns made of one, two, or three lentiform beams that span the whole intranuclear volume, pushing apart the chromatin. The input fibrils are no longer detectable inside the NIIs, where they become dominated by the aggregation of endogenous α-Syn. In addition to its phosphorylation at S129, α-Syn forming the NIIs acquires an epitope antibody reactivity profile that indicates its organization into fibrils, and is associated with the classical markers of α-Syn pathology p62 and ubiquitin. NIIs are also observed in vivo after intracerebral injection of the fibril strain in mice. Our data thus show that the ability to seed NIIs is a strain property that is integrally encoded in the fibril supramolecular architecture. Upstream alterations of cellular mechanisms are not required. In contrast to the lentiform TDP-43 NIIs, which are observed in certain frontotemporal dementias and which are conditional upon GRN or VCP mutations, our data support the hypothesis that the presence of α-Syn NIIs in MSA is instead purely amyloid-strain-dependent.
6 citations
References
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TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
8,452 citations
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Abstract: Lewy bodies, a defining pathological characteristic of Parkinson's disease and dementia with Lewy bodies (DLB)1,2,3,4, constitute the second most common nerve cell pathology, after the neurofibrillary lesions of Alzheimer's disease. Their formation may cause neurodegeneration, but their biochemical composition is unknown. Neurofilaments and ubiquitin are present5,6,7,8, but it is unclear whether they are major components of the filamentous material of the Lewy body9,10. Here we describe strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease11. α-Synuclein may be the main component of the Lewy body in Parkinson's disease. We also show staining for α-synuclein of Lewy bodies from DLB, indicating that the Lewy bodies from these two diseases may have identical compositions.
6,923 citations
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
5,440 citations
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
4,153 citations
National Institutes of Health1, Cardiff University2, VU University Amsterdam3, Erasmus University Rotterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Johns Hopkins University9, Georgetown University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations