bims-proned 2024-09-29 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–09–29
sixteen papers selected by
Verena Kohler, Umeå University

Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice.
Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.
Glycation Produces Topologically Different α-Synuclein Oligomeric Strains and Modulates Microglia Response via the NLRP3-Inflammasome Pathway.
Amyloid Fibril Formation on Neuronal Cells in the Coexistence of Aβ40 and Aβ42.
Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases.
Limitations and potential strategies of immune checkpoint blockade in age-related neurodegenerative disorders.
Intrinsic conformational preference in the monomeric protein governs amyloid polymorphism.
Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers.
Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology.
The role of liquid-liquid phase separation in the disease pathogenesis and drug development.
TDP-43 nuclear condensation and neurodegenerative proteinopathies.
Proteases: Role in Various Human Diseases.
Folding of N-terminally acetylated α-synuclein upon interaction with lipid membranes.
In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils.
Intercellular transmission of alpha-synuclein.
NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.

bioRxiv. 2024 Sep 14. pii: 2024.09.10.612226. [Epub ahead of print]

Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice.

Guo Xueshui, Ravindra Prajapati, Jiyeon Chun, Insuk Byun, Kamil K Gebis, Yi-Zhi Wang, Karen Ling, Casey Dalton, Jeff A Blair, Anahid Hamidianjahromi, Gemma Bachmann, Frank Rigo, Paymaan Jafar-Nejad, Jeffrey N Savas, Min Jae Lee, Jemeen Sreedharan, Robert G Kalb.

Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction in rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

DOI: https://doi.org/10.1101/2024.09.10.612226
J Zhejiang Univ Sci B. 2024 Sep 26. 1-5

Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.

Liwen Wang, Huimei Liu, Lanfang Li.

Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.

DOI: https://doi.org/10.1631/jzus.B2300853
ACS Chem Neurosci. 2024 Sep 25.

Glycation Produces Topologically Different α-Synuclein Oligomeric Strains and Modulates Microglia Response via the NLRP3-Inflammasome Pathway.

Manisha Kumari, Krishna Singh Bisht, Kriti Ahuja, Rajender K Motiani, Tushar Kanti Maiti.

  α-Synuclein, a key player in Parkinson's disease and other synucleinopathies, possesses an inherently disordered structure that allows for versatile structural changes during aggregation. Microglia, the brain immune cells, respond differently to various α-synuclein strains, influencing their activation and release of harmful molecules, leading to neuronal death. Post-translational modifications, such as glycation in α-synuclein, add a layer of complexity to microglial activation. This study aimed to explore the impact of glycation on α-synuclein aggregation and microglial responses, which have not been studied before. Biophysical analyses revealed that glycated α-synuclein oligomers had distinct morphologies with a more negative and hydrophobic surface, preventing fibril formation and interfering with membrane interactions. Notably, there was increased cytosolic Ca2+ dysregulation, redox stress, and mitochondrial instability compared to cells exposed to unmodified α-synuclein oligomers. Additionally, glycated α-synuclein oligomers exhibited impaired binding to Toll-like receptor 2, compromising downstream signaling. Surprisingly, these oligomers promoted TLR4 endocytosis and degradation. In our experiments with oligomers, glycated α-synuclein oligomers preferred NLRP3 inflammasome-mediated neuroinflammation, contributing differently from unmodified α-synuclein oligomers. In summary, this study unveils the mechanism underlying the effect of glycation on α-synuclein oligomers and highlights the conformation-specific microglial responses toward extracellular α-synuclein.

Keywords:  NOD- LRR- and pyrin domain-containing protein 3 (NLRP3); Parkinson’s disease; glycated α-synuclein; microglia; toll-like receptors 2; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.4c00057
Chembiochem. 2024 Sep 25. e202400603

Amyloid Fibril Formation on Neuronal Cells in the Coexistence of Aβ40 and Aβ42.

Mayu Kawaguchi, Kenichi Kawano, Aoi Taniguchi, Atsushi Tanaka, Katsumi Matsuzaki.

  The abnormal aggregation and subsequent deposition of amyloid β-protein (Aβ) in the brain are considered central to the pathogenesis of Alzheimer's disease. The two major species of Aβ are Aβ40 and Aβ42, present at an approximate ratio of 9: 1. Accumulating evidence suggests that neuronal membranes are an important platform of amyloidogenesis by Aβ. However, information on the aggregational behaviors of coexistent Aβ40 and Aβ42 on membranes is lacking. In this study, the aggregation and resultant cytotoxicity of coexistent Aβ40 and Aβ42 at a physiologically relevant ratio were investigated by fluorescence techniques. We found that the degree of coexistence of both Aβs in aggregates increased as the assembly proceeded, and reached a maximum in fibrils. However, the cytotoxicity of the mixed fibrils was weaker than that of Aβ42 fibrils, indicating that Aβ40 attenuates the toxicity of Aβ42 by forming mixed fibrils. In contrast, the degree of coexistence was significantly lower in aqueous phase aggregation, highlighting different aggregation mechanisms between in membranes and in the aqueous phase.

Keywords:  amyloid beta-peptides, cytotoxicity, fibril formation, fluorescence spectroscopy, membranes

DOI:  https://doi.org/10.1002/cbic.202400603
iScience. 2024 Sep 20. 27(9): 110828

Identification of proteotoxic and proteoprotective bacteria that non-specifically affect proteins associated with neurodegenerative diseases.

Alyssa C Walker, Rohan Bhargava, Michael J Bucher, Yoan M Argote, Amanda S Brust, Daniel M Czyż.

  There are no cures for neurodegenerative protein conformational diseases (PCDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Emerging evidence suggests the gut microbiota plays a role in their pathogenesis, though the influences of specific bacteria on disease-associated proteins remain elusive. Here, we reveal the effects of 229 human bacterial isolates on the aggregation and toxicity of Aβ1-42, α-synuclein, and polyglutamine tracts in Caenorhabditis elegans expressing these culprit proteins. Our findings demonstrate that bacterial effects on host protein aggregation are consistent across different culprit proteins, suggesting that microbes affect protein stability by modulating host proteostasis rather than selectively targeting disease-associated proteins. Furthermore, we found that feeding C. elegans proteoprotective Prevotella corporis activates the heat shock response, revealing an unexpected discovery of a microbial influence on host proteostasis. Insight into how individual bacteria affect PCD proteins could open new strategies for prevention and treatment by altering the abundance of microbes.

Keywords:  Bacteriology; Biological sciences; Molecular neuroscience; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.110828
J Physiol Sci. 2024 Sep 23. 74(1): 46

Limitations and potential strategies of immune checkpoint blockade in age-related neurodegenerative disorders.

Noha N Lasheen, Salma Allam, Abdullrahman Elgarawany, Darin W Aswa, Rana Mansour, Ziad Farouk.

  Neurological disorders such as Alzheimer's disease (AD), and Parkinson's disease (PD) have no disease-modifying treatments, resulting in a global dementia crisis that affects more than 50 million people. Amyloid-beta (Aβ), tau, and alpha-synuclein (α-Syn) are three crucial proteins that are involved in the pathogenesis of these age-related neurodegenerative diseases. Only a few approved AD medications have been used in the clinic up to this point, and their results are only partial symptomatic alleviation for AD patients and cannot stop the progression of AD. Immunotherapies have attracted considerable interest as they target certain protein strains and conformations as well as promote clearance. Immunotherapies also have the potential to be neuroprotective: as they limit synaptic damage and spread of neuroinflammation by neutralizing extracellular protein aggregates. Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aβ monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aβ) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aβ and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aβ (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate the therapeutic possibilities and adverse effects of these anti-Aβ and anti-αSyn MAbs on AD and PD.

Keywords:  Age-related neurodegenerative disorders; Alzheimer's disease; Immune checkpoint; Monoclonal antibodies; Parkinson's disease

DOI:  https://doi.org/10.1186/s12576-024-00933-4
Phys Chem Chem Phys. 2024 Sep 24.

Intrinsic conformational preference in the monomeric protein governs amyloid polymorphism.

Anjali Giri, Mily Bhattacharya.

The inherent stochasticity associated with the hierarchical self-assembly of either native-like or partially-unfolded protein monomers leads to the formation of transient, morphologically-diverse prefibrillar species resulting in structurally-distinct polymorphic protein aggregates. High-resolution structural characterization of mature aggregates has revealed heterogeneous supramolecular packing of protofibrils within amyloid polymorphs. However, little is known about whether initial monomeric protein conformers engender polymorphism at the onset of aggregation. Here, we show that intrinsic conformational preference in aggregation-competent monomeric ovalbumin, an archetypal serpin, dictates fibrillar polymorphism by modulating aggregation pathways. Using fluorescence, FT-IR, and vibrational Raman spectroscopy coupled with dynamic light scattering and electron microscopy, we demonstrate that conformationally-diverse amyloidogenic monomers, formed via an interplay of electrostatic and hydrophobic interactions before the commencement of aggregation, play a crucial role in promoting amyloid polymorphism. Moreover, the monomeric conformational fingerprints, accrued at the onset of aggregation, persist and propagate during the formation of polymorphic amyloids. Our results delineate essential conformational characteristics of the monomeric protein preceding aggregation, which will have broad implications in the mechanistic understanding of amyloid strain diversity observed in disease-related proteins.

DOI: https://doi.org/10.1039/d4cp01973c
Angew Chem Int Ed Engl. 2024 Sep 24. e202411942

Drug Discovery and Screening Tool Development for Tauopathies by Focusing on Pathogenic Tau Repeat 3 Oligomers.

Soljee Yoon, Hye Yun Kim, Sohui Park, Minhae Cha, Kyeonghwan Kim, Songmin Lee, JiMin Kim, Saeyun Bhang, YoungSoo Kim.

  Comprehending early amyloidogenesis is essential for the development of effective therapeutic strategies. In tauopathies like Alzheimer's disease (AD), the abnormal accumulation of tau protein is initiated by pathological tau seeds. Mounting evidence implies that the microtubule binding domain, consisting of three to four repeats, plays a pivotal role in this process, yet the exact region driving the formation of pathogenic species needs to be further scrutinized. Here, we chemically synthesized individual tau repeats to identify those exhibiting pathogenic prion-like characteristics. Notably, repeat 3 (R3) displayed a remarkable propensity to polymerize, form toxic filaments, and induce cognitive impairment, even in the absence of an aggregation-promoting inducer, highlighting its physiological relevance. Additionally, oligomeric R3 was identified as a particularly pathological form, prompting the establishment of a screening platform. Through screening, tolcapone was found to possess therapeutic efficacy against pathological tau aggregates in PS19 transgenic mice. This screening platform provides a valuable avenue for identifying compounds that selectively interact with peptides implicated in the progression of tauopathies.

Keywords:  Alzheimer's disease; High-Throughput Screening; Peptides; Tau protein; aggregation

DOI:  https://doi.org/10.1002/anie.202411942
J Am Chem Soc. 2024 Sep 27.

Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology.

Shenqing Zhang, Huaijiang Xiang, Youqi Tao, Juan Li, Shuyi Zeng, Qianhui Xu, Haonan Xiao, Shiran Lv, Caiwei Song, Yan Cheng, Martin Li, Zeyun Zhu, Shengnan Zhang, Bo Sun, Dan Li, ShengQi Xiang, Li Tan, Cong Liu.

The amyloid fibrils of α-synuclein (α-syn) are crucial in the pathology of Parkinson's disease (PD), with the intrinsically disordered region (IDR) of its C-terminal playing a key role in interacting with receptors like LAG3 and RAGE, facilitating pathological neuronal spread and inflammation. In this study, we identified Givinostat (GS) as an effective inhibitor that disrupts the interaction of α-syn fibrils with receptors such as LAG3 and RAGE through high-throughput screening. By exploring the structure-activity relationship and optimizing GS, we developed several lead compounds, including GSD-16-24. Utilizing solution-state and solid-state NMR, along with cryo-EM techniques, we demonstrated that GSD-16-24 binds directly to the C-terminal IDR of α-syn monomer and fibril, preventing the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly inhibits the association of α-syn fibrils with membrane receptors, thereby reducing neuronal propagation and pro-inflammatory effects of α-syn fibrils. Our findings introduce a novel approach to mitigate the pathological effects of α-syn fibrils by targeting their IDR with small molecules, offering potential leads for the development of clinical drugs to treat PD.

DOI: https://doi.org/10.1021/jacs.4c08869
Biomed Pharmacother. 2024 Sep 21. pii: S0753-3322(24)01334-9. [Epub ahead of print]180 117448

The role of liquid-liquid phase separation in the disease pathogenesis and drug development.

Yingjie Zhang, Chengkang Jin, Xiaoling Xu, Junping Guo, Lijun Wang.

  Misfolding and aggregation of specific proteins are associated with liquid-liquid phase separation (LLPS), and these protein aggregates can interfere with normal cellular functions and even lead to cell death, possibly affecting gene expression regulation and cell proliferation. Therefore, understanding the role of LLPS in disease may help to identify new mechanisms or therapeutic targets and provide new strategies for disease treatment. There are several ways to disrupt LLPS, including screening small molecules or small molecule drugs to target the upstream signaling pathways that regulate the LLPS process, selectively dissolve and destroy RNA droplets or protein aggregates, regulate the conformation of mutant protein, activate the protein degradation pathway to remove harmful protein aggregates. Furthermore, harnessing the mechanism of LLPS can improve drug development, including preparing different kinds of drug delivery carriers (microneedles, nanodrugs, imprints), regulating drug internalization and penetration behaviors, screening more drugs to overcome drug resistance and enhance receptor signaling. This review initially explores the correlation between aberrant LLPS and disease, highlighting the pivotal role of LLPS in preparing drug development. Ultimately, a comprehensive investigation into drug-mediated regulation of LLPS processes holds significant scientific promise for disease management.

Keywords:  Drug delivery carriers; Drug penetration; Drug release; Drug resistance; Enhancing receptor signaling; Liquid-liquid phase separation(LLPS)

DOI:  https://doi.org/10.1016/j.biopha.2024.117448
Trends Neurosci. 2024 Sep 25. pii: S0166-2236(24)00175-9. [Epub ahead of print]

TDP-43 nuclear condensation and neurodegenerative proteinopathies.

Florencia Vassallu, Lionel M Igaz.

  RNA-binding proteins (RBPs) can undergo phase separation and form condensates, processes that, in turn, can be critical for their functionality. In a recent study, Huang, Ellis, and colleagues show that cellular stress can trigger transient alterations in nuclear TAR DNA-binding protein 43 (TDP-43), leading to changes crucial for proper neuronal function. These findings have implications for understanding neurological TDP-43 proteinopathies.

Keywords:  RNA-binding protein; amyotrophic lateral sclerosis; frontotemporal dementia; membraneless organelles; neurodegenerative disease; phase condensation

DOI:  https://doi.org/10.1016/j.tins.2024.09.003
Curr Pharm Biotechnol. 2024 Sep 23.

Proteases: Role in Various Human Diseases.

Ogireddy Sri Apoorva, Khyati Shukla, Aakash Khurana, Nidhee Chaudhary.

  Proteases, a group of hydrolytic enzymes catalyzing the hydrolysis of peptide bonds, play pivotal roles in various physiological processes and have emerged as key contributors to the pathogenesis of diverse diseases. This work provides an insight into the impact of protease activity on different disease contexts, highlighting their involvement in cancer, inflammatory disorders, cardiovascular diseases, infectious diseases, and neurodegenerative conditions. In cancer, proteases facilitate tumor growth, invasion, and metastasis, while in inflammatory diseases, dysregulated protease activity exacerbates tissue damage and inflammation. Cardiovascular diseases involve proteases in extracellular matrix remodeling, affecting arterial structure. In infectious diseases, proteases play crucial roles in pathogen invasion and immune evasion. Neurodegenerative diseases are characterized by protease dysregulation, contributing to protein misfolding and aggregation. As research progresses, understanding the intricate relationships between proteases and diseases becomes essential for developing targeted therapeutic strategies. This review aims to provide a comprehensive glimpse into the diverse impact of protease activities on various diseases, emphasizing their potential as crucial players in the landscape of disease pathology and potential therapeutic interventions.

Keywords:  Proteases; cancer; cardiovascular diseases; infectious diseases; inflammatory diseases.; neurodegenerative diseases

DOI:  https://doi.org/10.2174/0113892010316162240910103659
Biophys J. 2024 Sep 20. pii: S0006-3495(24)00631-3. [Epub ahead of print]

Folding of N-terminally acetylated α-synuclein upon interaction with lipid membranes.

Zihan Tang, Zhou Fang, Xuwei Wu, Jie Liu, Liangfei Tian, Xuejin Li, Jiajie Diao, Baohua Ji, Dechang Li.

α-Synuclein (α-syn) is an abundant presynaptic neuronal protein whose aggregation is strongly associated with Parkinson's disease. It has been proposed that lipid membranes significantly affect the α-syn's aggregation process. Extensive studies have been conducted to understand the interactions between α-syn and lipid membranes and have demonstrated that the N-terminus plays a critical role. However, the dynamics of the interactions and the conformational transitions of the N-terminus of α-syn at the atomistic scale details are still highly desired. In this study, we performed extensive enhanced sampling molecular dynamics simulations to quantify the folding and interactions of wild-type (WT) and N-terminally acetylated (AC) α-syn when interacting with lipid structures. We found that N-terminal acetylation significantly increases the helicity of the first few residues in solution or when interacting with lipid membranes. The observations in simulations showed that the binding of α-syn with lipid membranes mainly follows the induced-fit model, where the disordered α-syn binds with the lipid membrane through the electrostatic interactions and hydrophobic contacts with the packing defects; after stable insertion, the N-terminal acetylation promotes the helical folding of the N-terminus to enhance the anchoring, thus increasing the binding affinity. We have shown the critical role of the first N-terminal residue methionine for recognition and anchoring to the negatively charged membrane. Although N-terminal acetylation neutralizes the positive charge of Met1 that may affect the electrostatic interactions of α-syn with membranes, the increase in helicity of the N-terminus should compensate for the binding affinity. This study provides detailed insight into the folding dynamics of α-syn's N-terminus with or without acetylation in solution and upon interaction with lipids, which clarifies how the N-terminal acetylation regulates the affinity of α-syn binding to lipid membranes. It also shows how packing defects and electrostatic effects co-regulate the N-terminus of α-syn folding and its interaction with membranes.

DOI: https://doi.org/10.1016/j.bpj.2024.09.019
bioRxiv. 2024 Sep 10. pii: 2024.09.09.612142. [Epub ahead of print]

In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils.

Shoyab Ansari, Dominique Lagasca, Rania Dumarieh, Yiling Xiao, Sakshi Krishna, Yang Li, Kendra K Frederick.

Amyloid forms of α-synuclein adopt different conformations depending on environmental conditions. Advances in structural biology have accelerated fibril characterization. However, it remains unclear which conformations predominate in biological settings because current methods typically not only require isolating fibrils from their native environments, but they also do not provide insight about flexible regions. To address this, we characterized α-syn amyloid seeds and used sensitivity enhanced nuclear magnetic resonance to investigate the amyloid fibrils resulting from seeded amyloid propagation in different settings. We found that the amyloid fold and conformational preferences of flexible regions are faithfully propagated in vitro and in cellular lysates. However, seeded propagation of amyloids inside cells led to the minority conformation in the seeding population becoming predominant and more ordered, and altered the conformational preferences of flexible regions. The examination of the entire ensemble of protein conformations in biological settings that is made possible with this approach may advance our understanding of protein misfolding disorders and facilitate structure-based drug design efforts.

DOI: https://doi.org/10.1101/2024.09.09.612142
Front Mol Neurosci. 2024 ;17 1470171

Intercellular transmission of alpha-synuclein.

Shenjie Wu, Randy W Schekman.

  An emerging theme in Parkinson's disease (PD) is the propagation of α-synuclein pathology as the disease progresses. Research involving the injection of preformed α-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of α-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for α-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of α-synuclein in extracellular vesicles.

Keywords:  Braak hypothesis; Parkinson’s disease; alpha synuclein; endosome escape; extracellular vesicle (EV); receptor-mediated uptake; tunneling nanotube; unconventional secretion

DOI:  https://doi.org/10.3389/fnmol.2024.1470171
PLoS Genet. 2024 Sep 23. 20(9): e1011411

NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.

Jonathan Plessis-Belair, Kathryn Ravano, Ellen Han, Aubrey Janniello, Catalina Molina, Roger B Sher.

Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTD\FTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.

DOI: https://doi.org/10.1371/journal.pgen.1011411