title: Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism.
abstract: Defects in synaptic development and plasticity may lead to autism. Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptogenesis and synaptic plasticity. BDNF is synthesized as a precursor, pro-BDNF, which can be processed into either a truncated form or into mature BDNF. Previous studies reported increased BDNF-immunoreactive protein in autism, but the mechanism of this increase has not been investigated. We examined BDNF mRNA by real-time reverse transcription-polymerase chain reaction and BDNF protein by Western blotting and enzyme-linked immunosorbent assay in postmortem fusiform gyrus tissue from 11 patients with autism and 14 controls. BDNF mRNA levels were not different in the autism versus control samples, but total BDNF-like immunoreactive protein, measured by enzyme-linked immunosorbent assay, was greater in autism than in controls. Western blotting revealed greater pro-BDNF and less truncated BDNF in autism compared with controls. These data demonstrate that increased levels of BDNF-immunoreactive protein in autism are not transcriptionally driven. Increased pro-BDNF and reduced truncated BDNF are consistent with defective processing of pro-BDNF to its truncated form. Distortion of the balance among the 3 BDNF isoforms, each of which may exhibit different biological activities, could lead to changes in connectivity and synaptic plasticity and, hence, behavior. Thus, imbalance in proteolytic isoforms is a possible new mechanism for altered synaptic plasticity leading to autism.
authors.affiliation: Departments of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kristine L P
authors.initials: KL
authors.lastname: Garcia
authors.forename: Guanhua
authors.initials: G
authors.lastname: Yu
authors.forename: Chiara
authors.initials: C
authors.lastname: Nicolini
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Michalski
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Garzon
authors.forename: Victor S
authors.initials: VS
authors.lastname: Chiu
authors.forename: Enrico
authors.initials: E
authors.lastname: Tongiorgi
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Margaret
authors.initials: M
authors.lastname: Fahnestock
mesh_terms: D000328:Adult; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000235:genetics; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D011498:Protein Precursors; D012333:RNA, Messenger; C426674:brain-derived neurotrophic factor precursor