Dataset Information

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS.

ABSTRACT: Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry.

SUBMITTER: Clark RM

PROVIDER: S-EPMC5353592 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1<sup>G93A</sup> mouse model of ALS.

Clark Rosemary M RM Blizzard Catherine A CA Young Kaylene M KM King Anna E AE Dickson Tracey C TC

Scientific reports 20170315

Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In t ...[more]

PMID: 28294153

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Project description:While the death of motor neuron is a pathological hallmark of amyotrophic lateral sclerosis (ALS), defects in other cell types or organs may also actively contribute to ALS disease progression. ALS patients experience progressive skeletal muscle wasting that may not only exacerbate neuronal degeneration, but likely has a significant impact on bone function. In our previous published study, we have discovered severe bone loss in an ALS mouse model with overexpression of ALS-associated mutation SOD1G93A (G93A). Here we further provide a mechanistic understanding of the bone loss in ALS animal and cellular models. Combining mitochondrial fluorescent indicators and confocal live cell imaging, we discovered abnormalities in mitochondrial network and dynamics in primary osteocytes derived from the same ALS mouse model G93A. Those mitochondrial defects occur in ALS mice after the onset of neuromuscular symptoms, indicating that mitochondria in bone cells respond to muscle atrophy during ALS disease progression. To examine whether ALS mutation has a direct contribution to mitochondrial dysfunction independent of muscle atrophy, we evaluated mitochondrial morphology and motility in cultured osteocytes (MLO-Y4) with overexpression of mitochondrial targeted SOD1G93A. Compared with osteocytes overexpressing the wild type SOD1 as a control, the SOD1G93A osteocytes showed similar defects in mitochondrial network and dynamic as that of the primary osteocytes derived from the ALS mouse model. In addition, we further discovered that overexpression of SOD1G93A enhanced the expression level of dynamin-related protein 1 (Drp1), a key protein promoting mitochondrial fission activity, and reduced the expression level of optic atrophy protein 1 (OPA1), a key protein related to mitochondrial fusion. A specific mitochondrial fission inhibitor (Mdivi-1) partially reversed the effect of SOD1G93A on mitochondrial network and dynamics, indicating that SOD1G93A likely promotes mitochondrial fission, but suppresses the fusion activity. Our data provide the first evidence that mitochondria show abnormality in osteocytes derived from an ALS mouse model. The accumulation of mutant SOD1G93A protein inside mitochondria directly causes dysfunction in mitochondrial dynamics in cultured MLO-Y4 osteocytes. In addition, the ALS mutation SOD1G93A-mediated dysfunction in mitochondrial dynamics is associated with an enhanced apoptosis in osteocytes, which could be a potential mechanism underlying the bone loss during ALS progression.

Project description:ALS (amyotrophic lateral sclerosis), the most common motor neuron disease, causes muscle denervation and rapidly fatal paralysis. While motor neurons are the most affected cells in ALS, studies on the pathophysiology of the disease have highlighted the importance of non-cell autonomous mechanisms, which implicate astrocytes and other glial cells. In ALS, subsets of reactive astrocytes lose their physiological functions and become toxic for motor neurons, thereby contributing to disease pathogenesis. Evidence of astrocyte contribution to disease pathogenesis are well established in cellular and animal models of familial ALS linked to mutant SOD1, where astrocytes promote motor neuron cell death. The mechanism underlying astrocytes reactivity in conditions of CNS injury have been shown to involve the MTOR pathway. However, the role of this conserved metabolic signaling pathway, and the potential therapeutic effects of its modulation, have not been investigated in ALS astrocytes. Here, we show elevated activation of the MTOR pathway in human-derived astrocytes harboring mutant SOD1, which results in inhibition of macroautophagy/autophagy, increased cell proliferation, and enhanced astrocyte reactivity. We demonstrate that MTOR pathway activation in mutant SOD1 astrocytes is due to post-transcriptional upregulation of the IGF1R (insulin like growth factor 1 receptor), an upstream positive modulator of the MTOR pathway. Importantly, inhibition of the IGF1R-MTOR pathway decreases cell proliferation and reactivity of mutant SOD1 astrocytes, and attenuates their toxicity to motor neurons. These results suggest that modulation of astrocytic IGF1R-MTOR pathway could be a viable therapeutic strategy in SOD1 ALS and potentially other neurological diseases.Abbreviations: ACM: astrocyte conditioned medium; AKT: AKT serine/threonine kinase; ALS: amyotrophic lateral sclerosis; BrdU: thymidine analog 5-bromo-2'-deoxyuridine; CNS: central nervous system; EIF4EBP1/4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; IGF1R: insulin like growth factor 1 receptor; INSR: insulin receptor; iPSA: iPSC-derived astrocytes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta;MTOR: mechanistic target of rapamycin kinase; NES: nestin; PPK1: 3-phosphoinositide dependent protein kinase 1; PI: propidium iodide; PPP: picropodophyllotoxin; PTEN: phosphatase and tensin homolog; S100B/S100β: S100 calcium binding protein B; SLC1A3/ EAAT1: solute carrier family 1 member 3; SMI-32: antibody to nonphosphorylated NEFH; SOD1: superoxide dismutase 1; TUBB3: tubulin beta 3 class III; ULK1: unc-51 like autophagy activating kinase 1.

Dataset Information

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS.

Publications

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1<sup>G93A</sup> mouse model of ALS.

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