Aberrant Control of Motoneuronal Excitability in Amyotrophic Lateral Sclerosis: Excitatory Glutamate / <scp>D</scp>‐Serine <i>vs.</i> Inhibitory Glycine/<i>γ</i>‐Aminobutanoic Acid (GABA)

Sasabe, Jumpei; Aiso, Sadakazu

doi:10.1002/cbdv.200900306

Cited by 18 publications

(6 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…119 Furthermore, metabolic disorders of d-Ser have been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). [120][121][122] ALS is the most common motor neuron disease and is clinically characterized by the coexistence of upper and lower motoneuronal signs with progressive neurological deterioration. 123 Classically, motoneurons are known to be vulnerable to glutamate excitotoxicity, which has long been implicated in sporadic and familial ALS.…”

Section: Metabolic Disorder Of Intrinsic D-amino Acids: Psychiatric Amentioning

confidence: 99%

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

Sasabe

Suzuki

2018

Keio J. Med.

Self Cite

View full text Add to dashboard Cite

Living organisms enantioselectively employ L-amino acids as the molecular architecture of protein synthesized in the ribosome. Although L-amino acids are dominantly utilized in most biological processes, accumulating evidence points to the distinctive roles of D-amino acids in non-ribosomal physiology. Among the three domains of life, bacteria have the greatest capacity to produce a wide variety of D-amino acids. In contrast, archaea and eukaryotes are thought generally to synthesize only two kinds of D-amino acids: D-serine and D-aspartate. In mammals, D-serine is critical for neurotransmission as an endogenous coagonist of N-methyl D-aspartate receptors. Additionally, D-aspartate is associated with neurogenesis and endocrine systems. Furthermore, recognition of D-amino acids originating in bacteria is linked to systemic and mucosal innate immunity. Among the roles played by D-amino acids in human pathology, the dysfunction of neurotransmission mediated by D-serine is implicated in psychiatric and neurological disorders. Non-enzymatic conversion of L-aspartate or L-serine residues to their D-configurations is involved in age-associated protein degeneration. Moreover, the measurement of plasma or urinary D-/L-serine or D-/L-aspartate levels may have diagnostic or prognostic value in the treatment of kidney diseases. This review aims to summarize current understanding of D-amino-acid-associated biology with a major focus on mammalian physiology and pathology.

show abstract

Section: Metabolic Disorder Of Intrinsic D-amino Acids: Psychiatric Amentioning

confidence: 99%

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

Sasabe

Suzuki

2018

Keio J. Med.

Self Cite

View full text Add to dashboard Cite

show abstract

“…An interesting study reported that Aβ‐induced NMDA‐mediated excitotoxicity was attenuated in SR knockout mice, which highlights the importance of D‐serine in neuronal excitotoxic mechanisms under the influence of astrocytes. Furthermore, SR activity and D‐serine levels were increased in SOD1 transgenic mice, resulting in enhanced NMDA‐mediated excitotoxic death of neurons …”

Section: Potential Factors That Disrupt Neuron‐astrocyte Interactionsmentioning

confidence: 99%

Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

Rao

Kielian

2015

Clinical & Exp Neuroim

View full text Add to dashboard Cite

Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron–astrocyte cross-talk in the context of select neurodegenerative diseases.

show abstract

“…Many theories implicate perturbations in glutamatergic neurotransmission, axonal transport, proteasome and protein integrity, mitochondria, oxidative stress, copper chemistry, apoptosis, and inflammation in the mechanisms of ALS pathogenesis [4, 5, 39 42]. Some theories have been springboards for drug trials, but all therapeutic trials, except two with Riluzole, have failed.…”

Section: Disease Mechanisms In Alsmentioning

confidence: 99%

“…One leading theory of ALS involves glutamate excitotoxicity [4, 42]. Reductions in the activity of glutamate transport occur in human sporadic ALS spinal cord [43] due to loss of astroglial glutamate transporter [44].…”

Section: Disease Mechanisms In Alsmentioning

confidence: 99%

“…The glutamate excitotoxicity and hyperexcitability theories of ALS emphasize the contribution of excessive synaptic excitation in part through AMPA receptors [4, 42, 73] and Na + channels [60, 67–69], while the possibility of insufficient synaptic inhibition has been theorized based on clinical data [127] but largely ignored experimentally. Abnormal GABA and glycine levels are observed in ALS patients [74, 75].…”

Section: Motoneurons In Als Have Deficient Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitory Synaptic Regulation of Motoneurons: A New Target of Disease Mechanisms in Amyotrophic Lateral Sclerosis

Martin

Chang

2011

Mol Neurobiol

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. It causes the degeneration of motoneurons and is fatal due to paralysis, particularly of respiratory muscles. ALS can be inherited, and specific disease-causing genes have been identified, but the mechanisms causing motoneuron death in ALS are not understood. No effective treatments exist for ALS. One well-studied theory of ALS pathogenesis involves faulty RNA editing and abnormal activation of specific glutamate receptors as well as failure of glutamate transport resulting in glutamate excitotoxicity; however, the excitotoxicity theory is challenged by the inability of anti-glutamate drugs to have major disease-modifying effects clinically. Nevertheless, hyperexcitability of upper and lower motoneurons is a feature of human ALS and transgenic (tg) mouse models of ALS. Motoneuron excitability is strongly modulated by synaptic inhibition mediated by presynaptic glycinergic and GABAergic innervations and postsynaptic glycine receptors (GlyR) and GABAA receptors; yet, the integrity of inhibitory systems regulating motoneurons has been understudied in experimental models, despite findings in human ALS suggesting that they may be affected. We have found in tg mice expressing a mutant form of human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, that subsets of spinal interneurons degenerate. Inhibitory glycinergic innervation of spinal motoneurons becomes deficient before motoneuron degeneration is evident in G93A-hSOD1 mice. Motoneurons in these ALS mice also have insufficient synaptic inhibition as reflected by smaller GlyR currents, smaller GlyR clusters on their plasma membrane, and lower expression of GlyR1α mRNA compared to wild-type motoneurons. In contrast, GABAergic innervation of ALS mouse motoneurons and GABAA receptor function appear normal. Abnormal synaptic inhibition resulting from dysfunction of interneurons and motoneuron GlyRs is a new direction for unveiling mechanisms of ALS pathogenesis that could be relevant to new therapies for ALS.

show abstract

Aberrant Control of Motoneuronal Excitability in Amyotrophic Lateral Sclerosis: Excitatory Glutamate / D‐Serine vs. Inhibitory Glycine/γ‐Aminobutanoic Acid (GABA)

Cited by 18 publications

References 120 publications

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

Inhibitory Synaptic Regulation of Motoneurons: A New Target of Disease Mechanisms in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About