Amyotrophic lateral sclerosis (ALS) is a progressive
neurodegenerative disease characterized by the loss of upper and lower motor
neurons, which eventually may lead to death. In spite of intensive research on
the molecular and cellular mechanisms involved in the etiology of ALS
initiation and progression, it is, unfortunately, poorly understood and there
is no efficient specific/decisive treatment for ALS patients. Critical to the
mission of developing effective therapies for ALS is the discovery of biomarkers
that can illuminate mechanisms of neurodegeneration and have diagnostic,
prognostic, or pharmacodynamic value. Here, we merged unbiased discovery-based
approaches and targeted quantitative comparative analyses to identify proteins
that are altered in cerebrospinal fluid (CSF) from patients with ALS. This
study aims to identify specific peptides in the cerebrospinal fluid (CSF) of
ALS patients and to examine their potential relevance to the etiology of this
disease. 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. 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 relevance 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. The mechanism
of action of the neurotoxic activity may be direct cytotoxicity to neuronal
cells causing necrotic/apoptotic effect and/or via LPS coactivation of
microglia and elicitation of inflammatory response resulting in neuronal
damage. Future studies are needed to explore the mechanism of action of these
neurotoxic peptides.
The results imply that two potentially neurotoxic peptides are
created, released, or penetrated the central nervous system during the
beginning and progression of ALS, causing neuroinflammation and
neurodegeneration.
Author
(s) Details
Uri Wormser
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The
Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Amnon Sintov
Department of Biomedical Engineering, Faculty of Engineering
Sciences, Ben Gurion University of the Negev, Be’er Sheva 84105, Israel.
Marco Vinceti
Department of Biomedical, Metabolic and Neural Sciences, University of
Modena and Reggio Emilia, 41125 Modena, Italy and Department of Epidemiology,
Boston University School of Public Health, Boston, MA 02118, USA.
Jessica Mandrioli
Department of Biomedical, Metabolic and Neural Sciences, Faculty of
Medicine and Surgery, University of Modena and Reggio Emilia, 41125 Modena,
Italy and Department of Neuroscience, Azienda Ospedaliero Universitaria di
Modena, 41126 Modena, Italy.
Berta Brodsky
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The
Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Elena Proscura
Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The
Hebrew University of Jerusalem, Jerusalem 9112002, Israel.
Yoram Finkelstein
Neurology and Toxicology Service and Unit, Shaare Zedek Medical Center,
Jerusalem 9103102, Israel.
Please see the book here:- https://doi.org/10.9734/bpi/mmrnp/v10/2348
