TY - JOUR
T1 - Unique cerebrospinal fluid peptides
T2 - potential amyotrophic lateral sclerosis biomarkers and etiological factors
AU - Wormser, Uri
AU - Sintov, Amnon
AU - Vinceti, Marco
AU - Mandrioli, Jessica
AU - Brodsky, Berta
AU - Proscura, Elena
AU - Finkelstein, Yoram
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023
Y1 - 2023
N2 - Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration.
AB - Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration.
KW - Amyotrophic lateral sclerosis
KW - motoneurons
KW - neuroinflammation
KW - osteopontin
KW - peptides
KW - transthyretin
UR - http://www.scopus.com/inward/record.url?scp=85207846957&partnerID=8YFLogxK
U2 - 10.37349/ent.2023.00060
DO - 10.37349/ent.2023.00060
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AN - SCOPUS:85207846957
SN - 2769-6510
VL - 3
SP - 435
EP - 445
JO - Exploration of Neuroprotective Therapy
JF - Exploration of Neuroprotective Therapy
IS - 6
ER -