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Review Article
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Neuropathogenesis-on-chips for neurodegenerative diseases
This review focuses on recent advances in on-chip platforms for patient-like in vitro modeling of the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic lateral sclerosis. The authors advocate for broader usage of these human-relevant models in the academic and pharmaceutical fields.
- Sarnai Amartumur
- , Huong Nguyen
- & Chaejeong Heo
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Article
| Open Access
PCDHA9 as a candidate gene for amyotrophic lateral sclerosis
Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.
- Jie Zhong
- , Chaodong Wang
- & Zhiheng Xu
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Article
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A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration
The etiology of TDP-43 proteinopathy in ALS and FTD is complex. Here, the authors show that prior to disease onset in the rNLS8 mouse model, cortex neurons elicit a transient increase in protective chaperones that combat TDP-43 aggregation.
- Rebecca San Gil
- , Dana Pascovici
- & Adam K. Walker
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Article
| Open Access
Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD
Intronic GGGGCC repeat expansion in the C9orf72 gene causes ALS/FTD. Here the authors show that mutant GGGGCC RNA triggers YY1-Fuzzy transcriptional dysregulation which subsequently induces Wnt/β-catenin pathway and activates cell death in C9ALS/FTD.
- Zhefan Stephen Chen
- , Mingxi Ou
- & Ho Yin Edwin Chan
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Article
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C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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Article
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Phenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA
GGGGCC repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. Here the authors show that CCCCGG antisense repeat RNA binds and inhibits phenylalanine-tRNA synthetase resulting in decreased levels of tRNAphe and phenylalanine rich proteins.
- Mirjana Malnar Črnigoj
- , Urša Čerček
- & Boris Rogelj
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Article
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Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation
Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients’ brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Junhao Li
- , Manoj K. Jaiswal
- & Stella Dracheva
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Article
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Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD
Hexanucleotide repeat expansion in the C9ORF72 gene produces toxic dipeptide repeat (DPR) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors apply single-molecule methods to study the translation dynamics of C9ORF72 expanded repeat in different frames showing that multiple translation steps contribute to the final toxic dipeptide production.
- Malgorzata J. Latallo
- , Shaopeng Wang
- & Bin Wu
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Article
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At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis
“In ALS clinical trials, efficacy is often assessed via subjective patient or clinician reports. The authors introduce a machine-learned severity score based on wearable sensor data from daily activities, which is reliable, sensitive, and could reduce clinical trial sizes.”
- Anoopum S. Gupta
- , Siddharth Patel
- & Fernando Vieira
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Article
| Open Access
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Neuroinflammation and autophagy are two pillars of ALS pathogenesis targeted by rapamycin. Here, in a randomized, double-blind, phase 2 clinical trial, the authors find rapamycin to be safe and well tolerated in ALS patients, supporting further studies.
- Jessica Mandrioli
- , Roberto D’Amico
- & Andrea Cossarizza
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Article
| Open Access
Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
The causes of ALS remain unclear with many proposed pathomechanisms. Here, the authors integrate iPSC-derived motor neuron and post-mortem datasets and identify a heightened DNA damage response accompanied by accumulation of somatic mutations in ALS.
- Oliver J. Ziff
- , Jacob Neeves
- & Rickie Patani
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Article
| Open Access
Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration
Expression of Drosophila or human endogenous retroviruses (ERVs) is sufficient to cause TDP-43 protein aggregation, and viral transmission of the ERVs triggers TDP-43 pathology in recipient cells. This mechanism may underly spread of neurodegenerative effects in a Drosophila model.
- Yung-Heng Chang
- & Josh Dubnau
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Article
| Open Access
Integrative genetic analysis illuminates ALS heritability and identifies risk genes
ALS is somewhat heritable, but the genetic basis is not completely understood. Here, the authors identify alterations in splicing in neurons associated with amyotrophic lateral sclerosis and uncover several associated genetic loci, with a potential link to nuclear pore defects.
- Salim Megat
- , Natalia Mora
- & Luc Dupuis
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Article
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Molecular subtypes of ALS are associated with differences in patient prognosis
Variability in ALS disease onset and progression are poorly understood. Our work identifies three distinct molecular states in post-mortem tissue that capture some of the observed differences in patient age of onset and survival.
- Jarrett Eshima
- , Samantha A. O’Connor
- & Barbara S. Smith
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Article
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T cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression
Amyotrophic lateral sclerosis (ALS) is a primary neurodegenerative disease, which is characterized by increased immune cell infiltration of the central nervous system. Here authors show that the phenotypic profile of T cells in the blood and cerebrospinal fluid of newly diagnosed ALS patients can predict disease progression, thus providing evidence that T cells contribute to disease pathology.
- Solmaz Yazdani
- , Christina Seitz
- & Fang Fang
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Article
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CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Here, the authors demonstrate CRISPR/Cas9 excision of the expansion results in a rescue of disease mechanisms in vivo and in vitro.
- Katharina E. Meijboom
- , Abbas Abdallah
- & Christian Mueller
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Article
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Intracellular energy controls dynamics of stress-induced ribonucleoprotein granules
Stress granules are associated with neurodegenerative diseases. Here, Wang et al. found intracellular energy deficiencies trigger a unique type of granules and disrupt granule disassembly through 4EBP1/eIF4A.
- Tao Wang
- , Xibin Tian
- & Jiou Wang
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Article
| Open Access
Stress induced TDP-43 mobility loss independent of stress granules
Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.
- Lisa Streit
- , Timo Kuhn
- & Karin M. Danzer
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Article
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Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion
Misfolded SOD1 has been linked to both familial and sporadic ALS. Here the authors have determined the cryo-EM structure of SOD1 fibrils, providing insights into the conversion of SOD1 from its immature form into an aggregated form during pathogenesis of ALS.
- Li-Qiang Wang
- , Yeyang Ma
- & Yi Liang
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Article
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NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
- Amanda M. Gleixner
- , Brandie Morris Verdone
- & Christopher J. Donnelly
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Article
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Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD
The GGGGCC repeat expansion in C9ORF72-ALS/FTD can be translated into five dipeptide repeat (DPR) proteins, including poly(GR) and poly(GA). Here, the authors develop assays to detect the levels of these DPR proteins in the CSF of individuals with ALS/FTD.
- Gopinath Krishnan
- , Denitza Raitcheva
- & Fen-Biao Gao
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Article
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Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
The expansion of GGGGCC repeats in the C9ORF72 gene results in the production of disease causing abnormal proteins with polymeric glycine-arginine (poly-GR) and polymeric proline-arginine (poly-PR). Here the authors demonstrate a structural mechanism of how poly-GR and poly-PR inhibit translation and how they might also perturb ribosome assembly.
- Anna B. Loveland
- , Egor Svidritskiy
- & Andrei A. Korostelev
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Article
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Spelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
The authors record neural firing rates in a patient with ALS in completely locked-in state and show that the patient can modulate neural firing rates based on auditory feedback to select letters to form words and phrases to communicate his needs and experiences.
- Ujwal Chaudhary
- , Ioannis Vlachos
- & Niels Birbaumer
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Article
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Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43
TDP-43 is a nucleic acid binding protein, whose insoluble aggregates are neuropathological hallmarks of specific subsets of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Post-translational modifications and acetylation of TDP-43 impact its interaction with RNA, its localization in the cells, and are linked to disease. Using antibodies generated against TDP-43 lysine acetylation sites, sirtuin-1 was found to potently deacetylate amber suppressed [acK136]TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding as well as phase separation and aggregation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
- Jorge Garcia Morato
- , Friederike Hans
- & Philipp J. Kahle
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Article
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Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
Here, the authors show in human iPSC-derived motor neurons from ALS patients and a TDP-43 mouse model that axonal TDP-43 forms G3BP1 positive RNP condensates, which sequester mRNA of nuclear encoded mitochondrial proteins and decrease local protein synthesis in motor neuron axons and neuromuscular junctions.
- Topaz Altman
- , Ariel Ionescu
- & Eran Perlson
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Article
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A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Yoshifumi Sonobe
- , Jihad Aburas
- & Paschalis Kratsios
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Article
| Open Access
Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
Organoids have improved disease modeling. Here, the authors generate human sensorimotor organoids derived from hiPSCs of individuals with ALS. These organoids contain skeletal muscle, sensory and motor neurons as well as astrocytes, microglia, and vasculature and form neuromuscular junctions.
- João D. Pereira
- , Daniel M. DuBreuil
- & Brian J. Wainger
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Article
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Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
The most frequent cause of familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are hexanucleotide repeat expansions in the non-coding region of the C9ORF72 gene that are translated into five dipeptide repeat (DPR) proteins. Here, the authors show that proline/arginine (PR) DPRs inhibit the prolyl isomerase PPIA and reveal the molecular mechanism of the impaired protein folding activity of PPIA by performing NMR measurements and determining a PR DPR bound PPIA crystal structure.
- Maria Babu
- , Filippo Favretto
- & Markus Zweckstetter
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Article
| Open Access
Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons
Here the authors show in a model of ALS that motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression is associated with specific loss of inhibitory synapses onto fast motor neurons.
- Ilary Allodi
- , Roser Montañana-Rosell
- & Ole Kiehn
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Article
| Open Access
Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS
Mutations in the RNA-binding protein FUS contribute to ALS. Here the authors use CLIP-seq on synaptoneurosomes to identify proteins associated with synapse organization and plasticity that are differentially regulated in a knock-in ALS mouse model.
- Sonu Sahadevan
- , Katharina M. Hembach
- & Magdalini Polymenidou
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Article
| Open Access
Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
- Jelena Scekic-Zahirovic
- , Inmaculada Sanjuan-Ruiz
- & Luc Dupuis
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Article
| Open Access
Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data
Genetic variation can impact protein complexes and interaction networks, but reconciling genetic and proteomic information remains challenging. To address this need, the authors develop Genoppi —a computational tool for integrating genetics and cell-type-specific proteomics data.
- Greta Pintacuda
- , Frederik H. Lassen
- & Kasper Lage
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Article
| Open Access
A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons
SFPQ is a splicing factor and its mutations are associated to amyotrophic lateral sclerosis (ALS) patients. Here, the authors show that SFPQ represses the use of pathogenic cryptic last exons in zebrafish, mouse and human cells.
- Patricia M. Gordon
- , Fursham Hamid
- & Corinne Houart
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Article
| Open Access
Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models
C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.
- Yuanjing Liu
- , Jean-Cosme Dodart
- & Robert H. Brown Jr.
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Article
| Open Access
Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow
Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.
- Vartika Mishra
- , Diane B. Re
- & Serge Przedborski
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Article
| Open Access
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
ALS is a neurodegenerative disease characterized by loss of motor neurons. Here, the authors showed that reduced levels of the VSP35 subunit in the retromer complex is a conserved ALS feature and identified a new lead compound increasing retromer stability ameliorating the disease phenotype.
- Luca Muzio
- , Riccardo Sirtori
- & Gianvito Martino
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Article
| Open Access
Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model
Astrocyte activation may contribute to neurodegenerative disease. Here the authors show that the combined knockout of three factors known to promote astrogliosis, IL-1α, TNFα and C1qa, leads to improved survival in the SOD1G93A mouse model of ALS.
- Kevin A. Guttenplan
- , Maya K. Weigel
- & Ben A. Barres
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Article
| Open Access
Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis
Neuroimmune interactions are important in amyotrophic lateral sclerosis (ALS). Here the authors characterize the role of NK cells in mouse models of ALS, and in patient tissue.
- Stefano Garofalo
- , Germana Cocozza
- & Cristina Limatola
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Article
| Open Access
Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons
Optogenetic approaches for inducing TDP-43 aggregation have been described previously in cellular models. Here the authors develop an approach to optogenetically induce TDP-43 aggregation in vivo using zebrafish to model ALS pathologies.
- Kazuhide Asakawa
- , Hiroshi Handa
- & Koichi Kawakami
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Article
| Open Access
Muscleblind acts as a modifier of FUS toxicity by modulating stress granule dynamics and SMN localization
The exact molecular mechanisms driving FUS-mediated toxicity remain unclear. Here, the authors demonstrate that muscleblind (Mbl) is a novel modifier of FUS-associated ALS, with knockdown of endogenous Mbl suppressing neuromuscular junction defects and motor dysfunctions associated with FUS expression in Drosophila, as well as restoring reduced SMN protein levels in mammalian neuronal and human iPSC-derived motor neurons.
- Ian Casci
- , Karthik Krishnamurthy
- & Udai Bhan Pandey
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Article
| Open Access
Transcription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD
Mechanisms of transcription of expanded G4C2 repeats in C9ORF72, associated with ALS/FTD, are not fully understood. Here authors use both Drosophila and C9ORF72 iPSC-derived neurons and identify AFF2/FMR2 as a regulator of poly(GR) toxicity by regulating expression of the expanded G4C2 repeats.
- Yeliz Yuva-Aydemir
- , Sandra Almeida
- & Fen-Biao Gao
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Article
| Open Access
First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound
MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
- Agessandro Abrahao
- , Ying Meng
- & Lorne Zinman
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Article
| Open Access
Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis
Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here, authors show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity and can be targeted to rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion
- Anthony Giampetruzzi
- , Eric W. Danielson
- & Claudia Fallini
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Article
| Open Access
Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1
The adaptor protein p11 and K+ channel TASK1 have overlapping distributions in the CNS. Here, the authors demonstrate that the transcription factor Sp1 regulates p11 levels, which in turn affects intrinsic membrane properties and can contribute to degeneration of motor neurons in disease and injury models.
- Victoria García-Morales
- , Guillermo Rodríguez-Bey
- & Bernardo Moreno-López
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Article
| Open Access
Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to disease manifestation in FTD/ALS associated with the hexanucleotide repeat expansion of the C9ORF72 gene. Here the authors show that a transgenic mouse line expressing poly-PR28 in neurons displays some signs of neuronal loss that mirrors that seen in the disease.
- Zongbing Hao
- , Liu Liu
- & Guanghui Wang
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Article
| Open Access
Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo
Cell-to-cell transmission of TDP43 occurs in cell cultures and may contribute to pathological TDP43 propagation in FTLD-TDP. In this study, the authors demonstrate using mouse models that a single intracerebral injection of human brain-derived pathological TDP43 from FTLD-TDP cases initiates the process of seeding and spreading of TDP43 pathology in a spatio-temporal dependent manner in the brain.
- Sílvia Porta
- , Yan Xu
- & Virginia M.-Y. Lee
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Article
| Open Access
Abnormal RNA stability in amyotrophic lateral sclerosis
RNA instability may be a contributing factor in amyotrophic lateral sclerosis (ALS). Here the authors carry out genome-wide assessment of RNA synthesis and stability in cells derived from patients with C9orf72 ALS, sporadic ALS and healthy controls.
- E. M. Tank
- , C. Figueroa-Romero
- & S. J. Barmada
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Article
| Open Access
A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy
Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.
- Maneka Chitiprolu
- , Chantal Jagow
- & Derrick Gibbings
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Article
| Open Access
A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to loss of voluntary muscle movement. Here, the authors screen for molecules that disrupt interaction between SOD1, a protein linked to ALS, and Derlin-1, and find an inhibitor that reduces pathology in an ALS mouse model.
- Naomi Tsuburaya
- , Kengo Homma
- & Hidenori Ichijo
Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia