title: Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown origins. Neurodegeneration in ALS mouse models occurs together with signs of disrupted blood-spinal cord barrier (BSCB) and regressed capillary network, but the molecular pathways contributing to these vascular pathologies remain unknown. We show that motor neurons of human sporadic ALS patients (n = 12) have increased gene expression of PDGFC and its activator PLAT and presymptomatic activation of the PDGF-CC pathway in SOD1 (G93A) mice leads to BSCB dysfunction. Decrease of Pdgfc expression in SOD1 (G93A) mice restored vascular barrier properties, reduced motor neuron loss and delayed symptom onset by up to 3 weeks. Similarly, lower expression levels of PDGFC or PLAT in motor neurons of sporadic ALS patients were correlated with older age at disease onset. PDGF-CC inhibition and restoration of BSCB integrity did not prevent capillary regression at disease end stage. Lower vessel density was found in spinal cords of sporadic ALS patients and the degree of regression in SOD1 (G93A) mice correlated with more aggressive progression after onset regardless of BSCB status. We conclude that PDGF-CC-induced BSCB dysfunction can contribute to timing of ALS onset, allow insight into disease origins and development of targeted novel therapies.
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden. sebastian.lewandowski@ki.se.
authors.forename: Sebastian A
authors.identifier: http://orcid.org/0000-0002-5935-0211
authors.initials: SA
authors.lastname: Lewandowski
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Nilsson
authors.affiliation: Vascular Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.|Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 7301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0644, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Fredriksson
authors.affiliation: Vascular Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönnerberg
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Muhl
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.
authors.forename: Manuel
authors.initials: M
authors.lastname: Zeitelhofer
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden.
authors.forename: Milena Z
authors.initials: MZ
authors.lastname: Adzemovic
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 17177, Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Nichterwitz
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 7301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-0644, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 17177, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hedlund
authors.affiliation: Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles v. 2, 17177, Stockholm, Sweden. ulf.pe.eriksson@ki.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D061346:Laser Capture Microdissection; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C
keywords: ALS; Blood–brain barrier; Cerebral blood flow; Neuroprotection; Small vessel disease