PMID- 33198383
OWN - NLM
STAT- MEDLINE
DCOM- 20210405
LR  - 20210405
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 22
DP  - 2020 Nov 12
TI  - A Novel HGF/SF Receptor (MET) Agonist Transiently Delays the Disease Progression 
      in an Amyotrophic Lateral Sclerosis Mouse Model by Promoting Neuronal Survival 
      and Dampening the Immune Dysregulation.
LID - 10.3390/ijms21228542 [doi]
LID - 8542
AB  - Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no 
      effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), 
      through its receptor MET, is one of the most potent survival-promoting factors 
      for motor neurons (MN) and is known as a modulator of immune cell function. We 
      recently developed a novel recombinant MET agonist optimized for therapy, 
      designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss 
      in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular 
      impairment and reduced MN loss and skeletal muscle denervation of superoxide 
      dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased 
      levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord 
      and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, 
      reduced activated microglia and astroglia, lower T cells infiltration and 
      increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 
      treated mice. K1K1 treatment also prevented the infiltration of T cells in 
      skeletal muscle of SOD1G93A mice. All these protective effects were lost on 
      long-term treatment suggesting a mechanism of drug tolerance. These data provide 
      a rational justification for further exploring the long-term loss of K1K1 
      efficacy in the perspective of providing a potential treatment for ALS.
FAU - Vallarola, Antonio
AU  - Vallarola A
AUID- ORCID: 0000-0001-7600-8058
AD  - Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di 
      Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
FAU - Tortarolo, Massimo
AU  - Tortarolo M
AD  - Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di 
      Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
FAU - De Gioia, Roberta
AU  - De Gioia R
AD  - Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di 
      Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
FAU - Iamele, Luisa
AU  - Iamele L
AD  - Immunology and General Pathology Unit, Department of Molecular Medicine, 
      Universita di Pavia, 27100 Pavia, Italy.
FAU - de Jonge, Hugo
AU  - de Jonge H
AD  - Immunology and General Pathology Unit, Department of Molecular Medicine, 
      Universita di Pavia, 27100 Pavia, Italy.
FAU - de Nola, Giovanni
AU  - de Nola G
AD  - Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Bovio, Enrica
AU  - Bovio E
AUID- ORCID: 0000-0002-7401-5622
AD  - Immunology and General Pathology Unit, Department of Molecular Medicine, 
      Universita di Pavia, 27100 Pavia, Italy.
FAU - Pasetto, Laura
AU  - Pasetto L
AD  - Laboratory of Translational Biomarkers, Department of Biochemistry and Molecular 
      Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, 
      Italy.
FAU - Bonetto, Valentina
AU  - Bonetto V
AD  - Laboratory of Translational Biomarkers, Department of Biochemistry and Molecular 
      Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, 
      Italy.
FAU - Freschi, Mattia
AU  - Freschi M
AD  - Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di 
      Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
FAU - Bendotti, Caterina
AU  - Bendotti C
AUID- ORCID: 0000-0003-1055-1271
AD  - Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di 
      Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.
FAU - Gherardi, Ermanno
AU  - Gherardi E
AD  - Immunology and General Pathology Unit, Department of Molecular Medicine, 
      Universita di Pavia, 27100 Pavia, Italy.
LA  - eng
GR  - SFMET-ALS/AriSLA/
GR  - 2015-0023/Regione Lombardia/
PT  - Journal Article
DEP - 20201112
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (HGF protein, human)
RN  - 0 (HGF protein, mouse)
RN  - 0 (Ligands)
RN  - 207137-56-2 (Interleukin-4)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/drug therapy/immunology/*metabolism
MH  - Animals
MH  - Astrocytes/cytology/metabolism
MH  - Behavior, Animal
MH  - Cell Survival
MH  - Coculture Techniques
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Dogs
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Gliosis/metabolism
MH  - Hepatocyte Growth Factor/*agonists
MH  - Humans
MH  - *Immune System
MH  - Interleukin-4/metabolism
MH  - Kringles
MH  - Ligands
MH  - Madin Darby Canine Kidney Cells
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Microglia/metabolism
MH  - Motor Neurons/metabolism
MH  - Neurons/*cytology/metabolism
MH  - Schwann Cells/metabolism
MH  - Spinal Cord/metabolism
MH  - T-Lymphocytes/cytology
PMC - PMC7696450
OTO - NOTNLM
OT  - HGF/SF
OT  - MET
OT  - SOD1G93A mice
OT  - T cells
OT  - amyotrophic lateral sclerosis
OT  - motor neurons
OT  - pERK
COIS- The authors declare no conflict of interest.
EDAT- 2020/11/18 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/11/01
CRDT- 2020/11/17 01:06
PHST- 2020/10/28 00:00 [received]
PHST- 2020/11/09 00:00 [revised]
PHST- 2020/11/10 00:00 [accepted]
PHST- 2020/11/17 01:06 [entrez]
PHST- 2020/11/18 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/11/01 00:00 [pmc-release]
AID - ijms21228542 [pii]
AID - ijms-21-08542 [pii]
AID - 10.3390/ijms21228542 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Nov 12;21(22):8542. doi: 10.3390/ijms21228542.