Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo

Qian, Kun; Huang, Hailong; Peterson, Andrew R.; Hu, Baoyang; Maragakis, Nicholas J.; Ming, Guo Li; Chen, Hong; Zhang, Su Chun

doi:10.1016/j.stemcr.2017.03.003

Cited by 112 publications

(99 citation statements)

References 41 publications

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“…; Qian et al . ), to our knowledge, no electrophysiological investigations have been reported in sporadic forms. Because mutations account for less than 20% ALS cases, and given the disappointing results of therapeutic translation (from mice to humans), there is a possibility that hypoexcitability is a specific feature of familial forms and animal models.…”

Section: Introductionmentioning

confidence: 76%

“…in motoneurons disconnected from the motor network). Furthermore, although motoneurons or astrocytes derived from sporadic ALS iPSCs exhibit similar characteristics to those derived from familial forms (Burkhardt et al 2013;Qian et al 2017), to our knowledge, no electrophysiological investigations have been reported in sporadic forms. Because mutations account for less than 20% ALS cases, and given the disappointing results of therapeutic translation (from mice to humans), there is a possibility that hypoexcitability is a specific feature of familial forms and animal models.…”

Section: Introductionmentioning

confidence: 86%

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Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Marchand‐Pauvert

Peyre

Lackmy-Vallée

et al. 2019

The Journal of Physiology

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Key points •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self‐sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration‐induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self‐sustained discharge, which is a sign of hypoexcitability. •∆F‐D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression. Abstract Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate‐induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty‐two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low‐threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F‐R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F‐D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F‐R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F‐D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self‐sustained discharge, and further supports that motoneurons are normo‐ to hypoexcitable in ALS patients, similar to observations in experimental models.

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Section: Introductionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 86%

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Marchand‐Pauvert

Peyre

Lackmy-Vallée

et al. 2019

The Journal of Physiology

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“…The increase in HSPB was not due to an increase in astrocyte numbers per se as GFAP and ALDH1 levels did not differ from controls. Astrocytes in ALS contain inclusions and exhibit an altered phenotype, likely contributing to motor neuron death . As astrogliosis may be a physiological response necessary for tissue repair as well as playing a pathogenic role, the actual role that HSPBs play in astrocytes during ALS remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

Gorter

Stephenson

Nutma

et al. 2018

Neuropathology Appl Neurobio

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Aims Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by progressive loss of motor neurons, muscle weakness, spasticity, paralysis and death usually within 2–5 years of onset. Neuroinflammation is a hallmark of ALS pathology characterized by activation of glial cells, which respond by upregulating small heat shock proteins (HSPBs), but the exact underlying pathological mechanisms are still largely unknown. Here, we investigated the association between ALS disease duration, lower motor neuron loss, TARDNA‐binding protein 43 (TDP‐43) pathology, neuroinflammation and HSPB expression. Methods With immunohistochemistry, we examined HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 expression in cervical, thoracic and sacral spinal cord regions in 12 ALS cases, seven with short disease duration (SDD), five with moderate disease duration (MDD), and ten age‐matched controls. Expression was quantified using ImageJ to examine HSP expression, motor neuron numbers, microglial and astrocyte density and phosphorylated TDP‐43 (pTDP‐43+) inclusions. Results SDD was associated with elevated HSPB5 and 8 expression in lateral tract astrocytes, while HSP16.2 expression was increased in astrocytes in MDD cases. SDD cases had higher numbers of motor neurons and microglial activation than MDD cases, but similar levels of motor neurons with pTDP‐43+ inclusions. Conclusions Increased expression of several HSPBs in lateral column astrocytes suggests that astrocytes play a role in the pathogenesis of ALS. SDD is associated with increased microgliosis, HSPB5 and 8 expression in astrocytes, and only minor changes in motor neuron loss. This suggests that the interaction between motor neurons, microglia and astrocytes determines neuronal fate and functional decline in ALS.

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“…Furthermore, it was also shown that astrocyte-like cells, isolated from postmortem spinal cord of sporadic ALS patients, highly expressed inflammatory mediators and caused neuronal toxicity when cocultured with ES derived neurons (Haidet-Phillips et al, 2011). When astrocytes derived from sporadic ALS patients were transplanted in the spinal cord of healthy mice, these showed lower presynaptic connections and impaired neuromuscular junctions (Kelley et al, 2018;Qian et al, 2017).…”

Section: Astrocytes In Alsmentioning

confidence: 99%

An update on human astrocytes and their role in development and disease

Majo

Koontz

Rowitch

et al. 2020

Glia

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Human astrocytes provide trophic as well as structural support to the surrounding brain cells. Furthermore, they have been implicated in many physiological processes important for central nervous system function. Traditionally astrocytes have been considered to be a homogeneous class of cells, however, it has increasingly become more evident that astrocytes can have very different characteristics in different regions of the brain, or even within the same region. In this review we will discuss the features of human astrocytes, their heterogeneity, and their generation during neurodevelopment and the extraordinary progress that has been made to model these fascinating cells in vitro, mainly from induced pluripotent stem cells. Astrocytes' role in disease will also be discussed with a particular focus on their role in neurodegenerative disorders. As outlined here, astrocytes are important for the homeostasis of the central nervous system and understanding their regional specificity is a priority to elucidate the complexity of the human brain.

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Sporadic ALS Astrocytes Induce Neuronal Degeneration In Vivo

Cited by 112 publications

References 41 publications

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

An update on human astrocytes and their role in development and disease

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