Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis

Almad, Akshata; Doreswamy, Arpitha; Gross, Sarah K.; Richard, Jean Philippe; Huo, Yuqing; Haughey, Norman J.; Maragakis, Nicholas J.

doi:10.1002/glia.22989

Cited by 124 publications

(145 citation statements)

References 62 publications

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“…Activated HCs have been involved in the release of gliotransmitters such as ATP and glutamate as well as chemokines that have deleterious consequences on neurons as reported in murine models of AD [18][19][20], experimental allergic encephalomyelitis [21], amyotrophic lateral sclerosis [20,22] and neuropathic pain [23,24]. In our study, it has also been demonstrated that activated HCs can allow Ca 2+ influx, contributing to a maintenance of high [Ca 2+ ]i.…”

Section: Commentarysupporting

confidence: 73%

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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CommentaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly and characterized by progressive memory loss, behavioral deficits and significant personality alterations [1,2]. The histopathological hallmarks of AD include Aβ plaques, neurofibrillary tangles, neuronal death and synapse loss. One significant feature of Aβ accumulation is the strong reactive gliosis associated with the Aβ plaques themselves [3,4], however, understanding of the properties and functions of astrocytes in AD has only begun to emerge in recent years.In the brain, astrocytes possess the highest levels of connexin (Cx) expression, with Cx43 and Cx30 being the most abundant [5,6]. Cxs are the proteins that form gap junction channels (GJCs) and hemichannels (HCs). Besides Cxs, HCs can be formed by another family of functionally related proteins, pannexins (Panxs), which share the same transmembrane topology as Cxs but have divergent primary sequences [7]. Cxs and Panxs oligomerize into hexameres that isolate a large non-selective pore in the membrane allowing for the diffusion of small molecules (e.g. ions, small signaling molecules and metabolic substrates) between the cell cytoplasm and the extracellular medium. In addition, most Cx HCs dock head-to-head between adjacent cells to form intercellular channels that constitute GJCs, while endogenously expressed Panx HCs do not [8,9]. In the brain, astrocytes provide trophic and metabolic support to neurons throughout the astrocytic network via gap junction communication which comprise of over several hundreds of astrocytes [10]. In brain pathologies, for instance in AD, reactive astrogliosis has been associated with changes in the expression and function of connexins. Increased expression of Cxs has been found in astrocytes that are in contact with amyloid plaques in vivo within the brains of AD patients and also in AD animal models. The most prominent indication of connexin changes in Alzheimer's disease is that increased immunoreactivity of Cx43 has been found at Aβ plaque levels in the post-mortem brains of AD patients, which coincides with the presence of gap junctions between astrocytic processes that are adjacent to dystrophic neuronal processes that are present in plaque areas at the ultrastructural level [11]. This Cx43 puncta enrichment has also been found within cadaveric brain sections from AD patients and is detected intermingled with strongly GFAP-positive astrocytic processes that infiltrate Aβ plaques [12]. These features have also been shown to be present in Cx30, though to a lower extent. This is also the case in AD animal models. In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled...

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Section: Commentarysupporting

confidence: 73%

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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“…Similarly to astrocytes (15,19,(32)(33)(34), however, we report that oligodendrocytes affect MNs through two distinct mechanisms of action: soluble factors and cell-to-cell contact, with the latter being more aggressive. Addition of lactate to the cocultures, in fact, does not rescue MNs.…”

Section: Discussionmentioning

confidence: 70%

Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism

Ferraiuolo

Meyer

Sherwood

et al. 2016

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

155

142

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Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.oligodendrocytes | amyotrophic lateral sclerosis | SOD1 | C9orf72 | lactate

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“…In mutant SOD1 animals, astrocyte Cx43 is significantly upregulated with disease progression, whereas oligodendrocyte Cx32 and Cx47 are downregulated (110,111). These changes in glial network activity through connexin hemichannels could contribute to the failure of remyelination and eventual demise of motor neurons.…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E Nmentioning

confidence: 99%

Oligodendroglia: metabolic supporters of neurons

Philips¹,

Rothstein²

2017

Journal of Clinical Investigation

260

192

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Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis

Cited by 124 publications

References 62 publications

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism

Oligodendroglia: metabolic supporters of neurons

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