An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na+-Activated K+Channels inAplysiaNeurons

Zhang, Yalan; Ni, Weiming; Horwich, Arthur L.; Kaczmarek, Leonard K.

doi:10.1523/jneurosci.3102-16.2017

Cited by 8 publications

(6 citation statements)

References 34 publications

(9 reference statements)

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“…Specifically, attenuation of excitability is supported by differences in the current-voltage relationship between WT and hSOD1 G93A mouse interneurons, and by the observation of reduced peak outward currents in hSOD1 G93A interneurons. Interestingly, outward potassium currents are affected in MNs derived from SOD1 ALS patients (Wainger et al, 2014 ), and by mutant SOD1 oligomers (Zhang et al, 2017 ), which could account for the changes in the hSOD1 G93A cortical interneurons.…”

Section: Discussionmentioning

confidence: 99%

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

Clark

Brizuela

Blizzard

et al. 2018

Front. Cell. Neurosci.

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Cortical interneurons play a crucial role in regulating inhibitory-excitatory balance in brain circuits, filtering synaptic information and dictating the activity of pyramidal cells through the release of GABA. In the fatal motor neuron (MN) disease, amyotrophic lateral sclerosis (ALS), an imbalance between excitation and inhibition is an early event in the motor cortex, preceding the development of overt clinical symptoms. Patients with both sporadic and familial forms of the disease exhibit reduced cortical inhibition, including patients with mutations in the copper/zinc superoxide-dismutase-1 (SOD1) gene. In this study, we investigated the influence of the familial disease-causing hSOD1-G93A ALS mutation on cortical interneurons in neuronal networks. We performed whole-cell patch-clamp recordings and neurobiotin tracing from GFP positive interneurons in primary cortical cultures derived from Gad67-GFP::hSOD1G93A mouse embryos. Targeted recordings revealed no overt differences in the passive properties of Gad67-GFP::hSOD1G93A interneurons, however the peak outward current was significantly diminished and cells were less excitable compared to Gad67-GFP::WT controls. Post hoc neurite reconstruction identified a significantly increased morphological complexity of the Gad67-GFP::hSOD1G93A interneuron neurite arbor compared to Gad67-GFP::WT controls. Our results from the SOD1 model suggest that cortical interneurons have electrophysiological and morphological alterations that could contribute to attenuated inhibitory function in the disease. Determining if these phenomena are driven by the network or represent intrinsic alteration of the interneuron may help explain the emergence of inhibitory susceptibility and ultimately disrupted excitability, in ALS.

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Section: Discussionmentioning

confidence: 99%

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

Clark

Brizuela

Blizzard

et al. 2018

Front. Cell. Neurosci.

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“…SOD1 G93A mouse diaphragm muscle NMJs were also found to be hyperexcitable pre-symptomatically (Rocha et al, 2013). This may be attributable to the same mechanisms by which oligomeric mutant SOD1 increases excitability through suppression of potassium currents in Aplysia californica ganglion (Zhang et al, 2017). An alternative cause of synaptic dysfunction at the muscle is that increased muscarinic sensitivity of perisynaptic Schwann cells in the SOD1 G37R mouse soleus impairs NMJ plasticity and repair (Arbour et al, 2015).…”

Section: Altered Neuronal Excitabilitymentioning

confidence: 98%

Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

Starr

Sattler

2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degeneration of upper and lower motor neurons, resulting in fatal paralysis due to denervation of the muscle. Due to genetic, pathological and symptomatic overlap, ALS is now considered a spectrum disease together with frontotemporal dementia (FTD), the second most common cause of dementia in individuals under the age of 65. Interestingly, in both diseases, there is a large prevalence of RNA binding proteins (RBPs) that are mutated and considered disease-causing, or whose dysfunction contribute to disease pathogenesis. The most common shared genetic mutation in ALS/FTD is a hexanucleuotide repeat expansion within intron 1 of C9ORF72 (C9). Three potentially overlapping, putative toxic mechanisms have been proposed: loss of function due to haploinsufficient expression of the C9ORF72 mRNA, gain of function of the repeat RNA aggregates, or RNA foci, and repeat-associated non-ATG-initiated translation (RAN) of the repeat RNA into toxic dipeptide repeats (DPRs). Regardless of the causative mechanism, disease symptoms are ultimately caused by a failure of neurotransmission in three regions: the brain, the spinal cord, and the neuromuscular junction. Here, we review C9 ALS/FTD-associated synaptic dysfunction and aberrant neuronal excitability in these three key regions, focusing on changes in morphology and synapse formation, excitability, and excitotoxicity in patients, animal models, and in vitro models. We compare these deficits to those seen in other forms of ALS and FTD in search of shared pathways, and discuss the potential targeting of synaptic dysfunctions for therapeutic intervention in ALS and FTD patients.

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“…proteins (e.g., mutant SOD1, FUS) and sporadic ALS-associated oxidized SOD1 protein all inhibited axonal transport via activation of a ASK1/P38 pathway, and ALS-associated mutant SOD1 protein inhibited synaptic transmission via the activation of ASK1-JNK pathway 30,49 .…”

Section: And Unpublished Observations) As Shown Previously Other Fami...mentioning

confidence: 99%

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats

Okekenwa,

Tsai,

Dooley

et al. 2023

Preprint

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Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but identifying specific toxic gene products and mechanisms has been difficult. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs), but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG (RAN) translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved downstream ASK1 signaling pathways that affect fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. These pathways are sufficient to produce the “dying-back” axonopathy seen in ALS. However, other mutant genes (e.g., SOD1) that activate this mechanism rarely produce FTD. When parallel studies in primary motor neurons from rats were conducted, an additional pathogenic mechanism was revealed. The GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclei of transfected neurons, leading to “dying-forward” neuropathy. All C9-DRP-mediated toxic effects observed here are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. These studies establish the divergent toxicity of C9-DPRs that cause neurodegeneration in ALS and FTD, suggesting that these two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with both ALS and FTD symptoms.Abstract FigureGraphic AbstractActivation of protein kinases and inhibition of axonal transport, synaptic transmission, and nuclear structure are toxic effects common to unrelated FALS-related gene products.FALS-related mutant forms of SOD1 (mSOD1), FUS (mFUS), and C9-GP-DPRs (GP(n)) activate specific ASK1-MAPK pathway. Within axons, active ASK1-p38 pathway phosphorylates various substrates, including conventional kinesin, leading to the inhibition of fast axonal transport mediated by the translocation of this motor protein along microtubules. ASK1 can also inhibit synaptic transmission via JNK activation. Both pathways cause reductions in the availability of critical synaptic cargoes, synaptic dysfunction, and “dying-back” degeneration of neurons. On the other hand, C9-PR and GR-DPRs (PR(n)and GR(n)) activate other pathways, leading to aberrant alterations in nuclear structure and function and “dying-forward” degeneration of neurons, consistent with reports of transcriptional changes and activation of apoptosis in ALS.

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An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na⁺-Activated K⁺Channels inAplysiaNeurons

Cited by 8 publications

References 34 publications

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

Synaptic dysfunction and altered excitability in C9ORF72 ALS/FTD

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats

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