Hyperexcitability, neurodegeneration, and disease progression in amyotrophic lateral sclerosis

Kiernan, Matthew C.; Park, Susanna B.

doi:10.1002/mus.27843

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…Evidence from human electrophysiological studies and ALS animal models strongly supports cortical hyperexcitability as important in the pathogenesis of ALS, occurring prior to the onset of the clinical syndrome [138,153]. There is a clear link between cortical hyperexcitability and subsequent downstream degeneration and loss of anterior horn cells [154,155]. Cortical hyperexcitability is a combined consequence of increased excitatory (glutamatergic) inputs to the upper motor neuron, paralleled by decreased inhibition mediated through GABAergic interneurons.…”

Section: Pathways To Als From Mnplsmentioning

confidence: 99%

Nanoplastics and Neurodegeneration in ALS

Eisen,

Pioro,

Goutman

et al. 2024

Brain Sciences

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Plastic production, which exceeds one million tons per year, is of global concern. The constituent low-density polymers enable spread over large distances and micro/nano particles (MNPLs) induce organ toxicity via digestion, inhalation, and skin contact. Particles have been documented in all human tissues including breast milk. MNPLs, especially weathered particles, can breach the blood–brain barrier, inducing neurotoxicity. This has been documented in non-human species, and in human-induced pluripotent stem cell lines. Within the brain, MNPLs initiate an inflammatory response with pro-inflammatory cytokine production, oxidative stress with generation of reactive oxygen species, and mitochondrial dysfunction. Glutamate and GABA neurotransmitter dysfunction also ensues with alteration of excitatory/inhibitory balance in favor of reduced inhibition and resultant neuro-excitation. Inflammation and cortical hyperexcitability are key abnormalities involved in the pathogenic cascade of amyotrophic lateral sclerosis (ALS) and are intricately related to the mislocalization and aggregation of TDP-43, a hallmark of ALS. Water and many foods contain MNPLs and in humans, ingestion is the main form of exposure. Digestion of plastics within the gut can alter their properties, rendering them more toxic, and they cause gut microbiome dysbiosis and a dysfunctional gut–brain axis. This is recognized as a trigger and/or aggravating factor for ALS. ALS is associated with a long (years or decades) preclinical period and neonates and infants are exposed to MNPLs through breast milk, milk substitutes, and toys. This endangers a time of intense neurogenesis and establishment of neuronal circuitry, setting the stage for development of neurodegeneration in later life. MNPL neurotoxicity should be considered as a yet unrecognized risk factor for ALS and related diseases.

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Section: Pathways To Als From Mnplsmentioning

confidence: 99%

Nanoplastics and Neurodegeneration in ALS

Eisen,

Pioro,

Goutman

et al. 2024

Brain Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

“…There is a clear link between it and subsequent downstream degeneration and loss of anterior horn cells. ( Kiernan and Park, 2023 ), Cortical hyperexcitability is a combined consequence of increased excitatory inputs to the upper motor neuron (UMN), paralleled by decreased inhibition, mediated through dysfunction of GABAergic interneurons fundamental to proper brain neural network functioning. The resulting imbalance in excitation/inhibition (E/I balance) is a feature shared by other neurodegenerative diseases ( Gunes et al, 2022 , Gunes et al, 2020 ).…”

Section: Site Of Als Onset – Competing Theoriesmentioning

confidence: 99%