Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

Wainger, Brian J.; Kiskinis, Evangelos; Mellin, Cassidy; Wiskow, Ole; Han, Steve S.W.; Sandoe, Jackson; Perez, Numa P.; Williams, Luis A.; Lee, Seungkyu; Boulting, Gabriella L.; Berry, James; Brown, Robert H.; Cudkowicz, Merit; Bean, Bruce P.; Eggan, Kevin; Woolf, Clifford J.

doi:10.1016/j.celrep.2014.03.019

Cited by 565 publications

(605 citation statements)

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“…Changes in intrinsic properties that make MNs hyperexcitable have been noted in neonatal slice preparations of ALS animals (29), as well as in MNs derived from iPS cells of ALS patients (15). Recent work in vivo, however, has questioned whether changes in intrinsic properties of MNs leads to hyperexcitability in adult animals (30).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the spinal cord becomes heavily myelinated in the first few weeks of postnatal life (13), making visualization of individual neurons difficult. Hence, most research regarding cellular electrophysiology in mouse models of ALS has been carried out with primary cultures of embryonic (E13-14) spinal cord MNs (14) or induced pluripotent stem (iPS) cell-derived MNs (15). Although they provide a basis for further study, these models may lack the changes that occur progressively in the context of an intact spinal cord.…”

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confidence: 99%

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Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Hadzipasic

Tahvildari

Nagy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) affects motor neurons (MNs) in the brain and spinal cord. Understanding the pathophysiology of this condition seems crucial for therapeutic design, yet few electrophysiological studies in actively degenerating animal models have been reported. Here, we report a novel preparation of acute slices from adult mouse spinal cord, allowing visualized whole cell patch-clamp recordings of fluorescent lumbar MN cell bodies from ChAT-eGFP or superoxide dismutase 1-yellow fluorescent protein (SOD1YFP) transgenic animals up to 6 mo of age. We examined 11 intrinsic electrophysiologic properties of adult ChAT-eGFP mouse MNs and classified them into four subtypes based on these parameters. The subtypes could be principally correlated with instantaneous (initial) and steady-state firing rates. We used retrograde tracing using fluorescent dye injected into fast or slow twitch lower extremity muscle with slice recordings from the fluorescent-labeled lumbar MN cell bodies to establish that fast and slow firing MNs are connected with fast and slow twitch muscle, respectively. In a G85R SOD1YFP transgenic mouse model of ALS, which becomes paralyzed by 5-6 mo, where MN cell bodies are fluorescent, enabling the same type of recording from spinal cord tissue slices, we observed that all four MN subtypes were present at 2 mo of age. At 4 mo, by which time substantial neuronal SOD1YFP aggregation and cell loss has occurred and symptoms have developed, one of the fast firing subtypes that innvervates fast twitch muscle was lost. These results begin to describe an order of the pathophysiologic events in ALS.neurodegeneration | motor neurons | amyotrophic lateral sclerosis | electrophysiology A myotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive and usually lethal neurodegenerative condition prominently featuring loss of motor neurons (MNs) and muscle denervation (1-3). Inherited forms of ALS, accounting for ∼10% of cases, potentially inform about disease mechanisms, including: protein folding and quality control [e.g., mutant superoxide dismutase 1 (SOD1), ubiquilin2, and VCP]; RNA binding proteins (e.g., TDP43, FUS, and HNRNPA1); or a DNA expansion (C9ORF72 hexanucleotide expansion). The clinical courses of the various heritable forms and the 90% of cases that are considered sporadic are not distinct, however, reflecting a potentially shared progressive loss of MNs and motor circuit dysfunction (4).ALS has been modeled in mice that are transgenic for a variety of mutant forms of SOD1, allowing for the study of the trajectory of the condition at various time points (5, 6). Among the studies conducted to date are a number addressing electrophysiological changes. From these studies, however, there does not appear to be a clear consensus on the changes that occur in MNs before and during the development of symptoms (7). For example, whereas research on the neuromuscular junction has revealed preferential denervation of fast twitch (type IIb) muscle fibers (8-10), t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Hadzipasic

Tahvildari

Nagy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…If so, this innovative technology could be used to screen potential candidates for a clinical trial. Recently, we found that the hyperexcitability of iPS-MNs from people with ALS normalized upon application of a potassium channel activator, retigabine [52]. Based on this science, a human trial of retigabine for ALS will soon be underway, with outcome measures of neuronal hyperexcitability, including transcranial magnetic stimulation.…”

Section: Retigabine: a Case Study For Innovative Als Clinical Trial Dmentioning

confidence: 98%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

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“…Although there is some discrepancy between different studies, it seems that patientderived motor neurons, regardless of the specific mutation they carry, display clear electrophysiological abnormalities. Wainger et al, in fact, using multi-electrode array and patch clamp recordings report that hyperexcitability is an intrinsic characteristic of iPSCderived motor neurons harbouring SOD1, C9orf72 and fused in sarcoma (FUS) mutations (47). Very recently, a breakthrough has identified a new molecular mechanism that may contribute to C9orf72-mediated pathogenic mechanism.…”

Section: Human Escs and Ipscsmentioning

confidence: 99%

“…Observations from other neurological disorders, such as Alzheimer's (62) and Parkinson's disease (63), show a similar trend as what we have observed in ALS. A very elegant recent study (64) has provided important information that might explain why iPSC-derived neurons and glia might display mild signs of pathology (39,50,54,47). RNA-Sequencing analysis of fibroblasts, iPSCs, iPSC-derived neurons, neurons reprogrammed directly from fibroblasts (iNeurons) and post-mortem brain tissues revealed that iPSC-derived neurons lose their aging signatures.…”

Section: The Promises and Limitations Of Cell Reprogrammingmentioning

confidence: 99%

New In Vitro Models to Study Amyotrophic Lateral Sclerosis

Myszczynska

Ferraiuolo

2016

Brain Pathology

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Amyotrophic Lateral Sclerosis (ALS) is a complex multifactorial disorder, characterized by motor neuron loss with involvement of several other cell types, including astrocytes, oligodendrocytes and microglia. Studies in vivo and in in vitro models have highlighted that the contribution of nonneuronal cells to the disease is a primary event and ALS pathogenesis is driven by both cell-autonomous and non-cell autonomous mechanisms. The advancements in genetics and in vitro modeling of the past 10 years have dramatically changed the way we investigate the pathogenic mechanisms involved in ALS. The identification of mutations in transactive response DNA-binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease. In the same years, from 2007 to present, in vitro technologies to model neurological disorders have also undergone impressive developments. The advent of induced pluripotent stem cells (iPSCs) gave the field of ALS the opportunity to finally model in vitro not only familial, but also the larger part of ALS cases affected by sporadic disease. Since 2008, when the first human iPS-derived motor neurons from patients were cultured in a petri dish, several different techniques have been developed to produce iPSC lines through genetic reprogramming and multiple direct conversion methods have been optimised. In this review we will give an overview of how human in vitro models have been used so far, what discoveries they have led to since 2007, and how the recent advances in technology combined with the genetic discoveries, have tremendously widened the horizon of ALS research.

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Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

Cited by 565 publications

References 48 publications

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

New In Vitro Models to Study Amyotrophic Lateral Sclerosis

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