Neuropathology of partial pgc-1? deficiency recapitulates features of mitochondrial encephalopathies but not of neurodegenerative diseases

Abstract

Background: Deficient peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) 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-1? 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-1? protein (FL-PGC-1?) but expressing an N-truncated fragment. Methods: To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, ?-synuclein, amyloid-?, 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 per-formed an anatomical mapping to provide a lesion profile. Results: The immunohistochemical pattern of neurodegeneration-related proteins did not differ between FL-PGC-1? 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. Conclusion: We conclude that the lack of FL-PGC-1? per se is insufficient to recapitulate major features of neurodegenerative diseases, but evokes a pathology seen in mitochondrial encephalopathies, which makes PGC-1?-deficient mice a valuable model for this yet incurable group of diseases. Copyright © 2013 S. Karger AG, Basel.