title: Neuropathology of partial PGC-1α deficiency recapitulates features of mitochondrial encephalopathies but not of neurodegenerative diseases.
abstract: BACKGROUND
  Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one component of mitochondrial dysfunction in neurodegenerative diseases. Current molecular classification of such diseases is based on the predominant protein accumulating as intra- or extracellular aggregates. Experimental evidence suggests that mitochondrial dysfunction and impaired protein processing are closely interrelated. In vitro findings further indicate that PGC-1α dysfunction may contribute to protein misfolding in neurodegeneration.
  
  
  OBJECTIVE
  To systematically evaluate the neuropathological alterations of mice lacking the expression of the full-length PGC-1α protein (FL-PGC-1α) but expressing an N-truncated fragment.
  
  
  METHODS
  To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, α-synuclein, amyloid-β, amyloid precursor protein, prion protein, FUS, TDP-43 and ubiquitin. Using hematoxylin and eosin, Klüver-Barrera and Bielschowsky silver stainings and anti-GFAP immunohistochemistry, we performed an anatomical mapping to provide a lesion profile.
  
  
  RESULTS
  The immunohistochemical pattern of neurodegeneration-related proteins did not differ between FL-PGC-1α knockout and wild-type animals, and there was a complete lack of protein deposits or ubiquitin-positive inclusions. The analysis of neuropathological alterations revealed widespread vacuolation predominating in the cerebral white matter, caudate-putamen, thalamus and brainstem, and reactive astrogliosis in the brainstem and cerebellar nuclei. This morphological phenotype was thus reminiscent of human mitochondrial encephalopathies, especially the Kearns-Sayre syndrome.
  
  
  CONCLUSIONS
  We conclude that the lack of FL-PGC-1α per se is insufficient to recapitulate major features of neurodegenerative diseases, but evokes a pathology seen in mitochondrial encephalopathies, which makes PGC-1α-deficient mice a valuable model for this yet incurable group of diseases.
authors: Department of Neurology, University of Szeged, Szeged, Hungary.
authors: Levente
authors: L
authors: Szalardy
authors: Denes
authors: D
authors: Zadori
authors: Imola
authors: I
authors: Plangar
authors: Laszlo
authors: L
authors: Vecsei
authors: Patrick
authors: P
authors: Weydt
authors: Albert C
authors: AC
authors: Ludolph
authors: Peter
authors: P
authors: Klivenyi
authors: Gabor G
authors: GG
authors: Kovacs
mesh_terms: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011328:Prions; D034702:RNA-Binding Protein FUS; D016622:Silver Staining; D014157:Transcription Factors / Q000172:deficiency*; D025801:Ubiquitin; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011328:Prions; D034702:RNA-Binding Protein FUS; D014157:Transcription Factors; D025801:Ubiquitin; D051844:alpha-Synuclein; D016875:tau Proteins