TDP-43 is intercellularly transmitted across axon terminals

Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43–containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma “horizontal” and bidirectional “vertical” synaptic intercellular transmission and prion-like seeding of TDP-43.

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Macroscopic Localized Subicular Thinning as a Potential Indicator of Amyotrophic Lateral Sclerosis

European Neurology ◽

10.1159/000487992 ◽

2018 ◽

Vol 79 (3-4) ◽

pp. 200-205 ◽

Cited By ~ 2

Author(s):

Hiroki Yamada ◽

Takahiro Takeda ◽

Toshiki Uchihara ◽

Shizuko Sato ◽

Susumu Kirimura ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Nucleus Accumbens ◽

Dna Binding ◽

Alzheimer Disease ◽

Binding Protein ◽

Dna Binding Protein ◽

Potential Indicator ◽

Transentorhinal Cortex ◽

Als Patients ◽

Lateral Sclerosis

Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients. Macroscopic subicular thinning and corresponding astrocytosis were pronounced in ALS compared to AD. This thinning was frequently accompanied by TDP-43 pathology in the transentorhinal cortex and nucleus accumbens. The preferential susceptibility of the perforant pathway to TDP-43 deposition may be an underlying cause of subicular thinning in ALS.

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The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology

Molecular and Cellular Biology ◽

10.1128/mcb.00243-18 ◽

2018 ◽

Vol 38 (19) ◽

Cited By ~ 5

Author(s):

Yasar Arfat T. Kasu ◽

Samrawit Alemu ◽

Angela Lamari ◽

Nicole Loew ◽

Christopher S. Brower

Keyword(s):

Amino Acids ◽

Amyotrophic Lateral Sclerosis ◽

Dna Binding ◽

Binding Protein ◽

Ubiquitin Proteasome System ◽

Dna Binding Protein ◽

Aggregation Propensity ◽

Ubiquitin Proteasome ◽

Intracellular Aggregates ◽

Lateral Sclerosis

ABSTRACTFragments of the TAR DNA-binding protein 43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exist, with distinct N termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Previously, we found that specific CTFs accumulate in the absence of the Arg/N-end rule pathway of the ubiquitin proteasome system (UPS) and that their degradation requires arginyl-tRNA protein transferase 1 (ATE1). Here, we examined two specific CTFs of TDP43 (TDP43219and TDP43247), which are ∼85% identical and differ at their N termini by 28 amino acids. We found that TDP43247is degraded primarily by the Arg/N-end rule pathway, whereas degradation of TDP43219continues in the absence of ATE1. These fragments also differ in their aggregation propensities and form morphologically distinct aggregates. This work reveals that the N termini of otherwise similar CTFs have profound effects on fragment behavior and may influence clinical outcomes in neurodegeneration associated with aggregation.

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TDP-43 and HERV-K Envelope-Specific Immunogenic Epitopes Are Recognized in ALS Patients

Viruses ◽

10.3390/v13112301 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2301

Author(s):

Elena Rita Simula ◽

Giannina Arru ◽

Ignazio Roberto Zarbo ◽

Paolo Solla ◽

Leonardo A. Sechi

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Humoral Response ◽

Dna Binding Protein ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Healthy Controls ◽

Newly Diagnosed ◽

Als Patients ◽

Circulating Levels ◽

Lateral Sclerosis

The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes’ fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.

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Passive Transfer of Blood Sera from ALS Patients with Identified Mutations Results in Elevated Motoneuronal Calcium Level and Loss of Motor Neurons in the Spinal Cord of Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22189994 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9994

Author(s):

Tamás F. Polgár ◽

Valéria Meszlényi ◽

Bernát Nógrádi ◽

Laura Körmöczy ◽

Krisztina Spisák ◽

...

Keyword(s):

Motor Neurons ◽

Calcium Level ◽

Chromosome 9 ◽

Control Group ◽

Similar Treatment ◽

Reading Frame ◽

Axon Terminals ◽

Optical Disector ◽

Als Patients ◽

Lateral Sclerosis

Introduction: Previously, we demonstrated the degeneration of axon terminals in mice after repeated injections of blood sera from amyotrophic lateral sclerosis (ALS) patients with identified mutations. However, whether a similar treatment affects the cell body of motor neurons (MNs) remained unresolved. Methods: Sera from healthy individuals or ALS patients with a mutation in different ALS-related genes were intraperitoneally injected into ten-week-old male Balb/c mice (n = 3/serum) for two days. Afterward, the perikaryal calcium level was measured using electron microscopy. Furthermore, the optical disector method was used to evaluate the number of lumbar MNs. Results: The cytoplasmic calcium level of the lumbar MNs of the ALS-serum-treated mice, compared to untreated and healthy-serum-treated controls, was significantly elevated. While injections of the healthy serum did not reduce the number of MNs compared to the untreated control group, ALS sera induced a remarkable loss of MNs. Discussion: Similarly to the distant motor axon terminals, the injection of blood sera of ALS patients has a rapid degenerative effect on MNs. Analogously, the magnitude of the evoked changes was specific to the type of mutation; furthermore, the degeneration was most pronounced in the group treated with sera from ALS patients with a mutation in the chromosome 9 open reading frame 72 gene.

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Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

Current Neurovascular Research ◽

10.2174/1567202617666200409125227 ◽

2020 ◽

Vol 17 (3) ◽

pp. 275-285 ◽

Cited By ~ 5

Author(s):

Si Chen ◽

Qiao Liao ◽

Ke Lu ◽

Jinxia Zhou ◽

Cao Huang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rat Model ◽

Microglial Activation ◽

Transgenic Rat ◽

Intragastric Administration ◽

Behavioral Deficits ◽

Als Patients ◽

Lateral Sclerosis ◽

Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200583 ◽

2021 ◽

pp. 1-5

Author(s):

João Morgadinho ◽

Ana Catarina Pronto-Laborinho ◽

Vasco A. Conceição ◽

Marta Gromicho ◽

Susana Pinto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Creatinine Level ◽

Cox Regression ◽

Functional Decline ◽

Plasma Creatinine ◽

Plasma Creatinine Level ◽

Decline Rate ◽

Respiratory Outcome ◽

Als Patients ◽

Lateral Sclerosis

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

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Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review

Journal of Neurology ◽

10.1007/s00415-021-10472-2 ◽

2021 ◽

Author(s):

Georgiana Soares Leandro ◽

Mário Emílio Teixeira Dourado Júnior ◽

Glauciane Costa Santana ◽

Luan Samy Xavier Dantas

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Coping Strategies ◽

Integrative Review ◽

Als Patients ◽

Lateral Sclerosis

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Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

Brain Sciences ◽

10.3390/brainsci11070906 ◽

2021 ◽

Vol 11 (7) ◽

pp. 906

Author(s):

Nimeshan Geevasinga ◽

Mehdi Van den Bos ◽

Parvathi Menon ◽

Steve Vucic

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Excitability ◽

Muscular Atrophy ◽

Close Relationship ◽

Bulbar Onset ◽

Als Patients ◽

Transcranial Magnetic Simulation ◽

Cortical Dysfunction ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

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Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽

10.3390/diagnostics11071210 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1210

Author(s):

Júlia Costa ◽

Marta Gromicho ◽

Ana Pronto-Laborinho ◽

Conceição Almeida ◽

Ricardo A. Gomes ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Motor Neurons ◽

Neurological Diseases ◽

Disease Diagnosis ◽

Enzyme Linked Immunosorbent Assay ◽

Progression Rate ◽

Therapeutic Trials ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

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