ABSTRACT
BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose-dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax ) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3-5 vs. 5-8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.
Subject(s)
Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Glycine/cerebrospinal fluid , Nootropic Agents/pharmacology , Organic Chemicals/pharmacology , Administration, Oral , Adult , Alzheimer Disease/drug therapy , Animals , Area Under Curve , Cell Line , Dose-Response Relationship, Drug , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Healthy Volunteers , Humans , Male , Middle Aged , Neurons , Nootropic Agents/pharmacokinetics , Nootropic Agents/therapeutic use , Organic Chemicals/administration & dosage , Organic Chemicals/pharmacokinetics , Primary Cell Culture , Rats , Rats, Wistar , Schizophrenia/drug therapy , Young AdultABSTRACT
Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.
Subject(s)
Multiple System Atrophy/genetics , Multiple System Atrophy/metabolism , Oligodendroglia/metabolism , alpha-Synuclein/genetics , fas Receptor/metabolism , Aged , Animals , Brain/metabolism , Brain/pathology , Cell Death/drug effects , Fas Ligand Protein/metabolism , Fas Ligand Protein/toxicity , Gene Expression , Humans , Mice , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oligodendroglia/drug effects , Protein Binding , Protein Transport , Rats , Signal Transduction , alpha-Synuclein/metabolismABSTRACT
(Oligodendro)glial cytoplasmic inclusions composed of the protein alpha-synuclein (alphaSYN) are the neuropathological hallmark lesions of multiple system atrophy (MSA). The recent generation of transgenic mouse models of oligodendroglial alpha-synucleinopathy has enabled studies to investigate how alphaSYN causally contributes to MSA neuropathology. Moreover, human disease-specific pathological modifications of alphaSYN were recapitulated in transgenic mice, including insolubility, phosphorylation at serine-129, and ubiquitination. Thus, the transgenic mice will be useful tools to assess cellular risk factors, such as protein folding stress, protein kinase hyperactivity, and failure of the ubiquitin-proteasome system. Moreover, transgenic mice expressing a hyperactive alpha(1B)-adrenergic receptor mutant showed evidence of alphaSYN pathology in oligodendrocytes, adding dysregulated adrenergic neurotransmission to the list of potential risk factors of MSA. Finally, a double-transgenic mouse model expressing both alphaSYN and tau revealed synergistic fibrillization of these two proteins, providing an animal model for the not uncommon neuropathological finding of concomitant alpha-synucleinopathy and tauopathy within oligodendrocytes. Despite the progress made modeling MSA neuropathology in the transgenic mouse models, the molecular mechanism of how alphaSYN aggregation in oligodendrocytes causes neurodegeneration remains to be established. Moreover, it will be important to understand what defines the predilection sites most severely affected by striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C), respectively.
