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Neuropathology of Partial PGC-1alpha Deficiency Recapitulates Features of Mitochondrial Encephalopathies but Not of Neurodegenerative Diseases.

Authors: Szalardy, L  Zadori, D  Plangar, I  Vecsei, L  Weydt, P  Ludolph, AC  Klivenyi, P  Kovacs, GG 
Citation: Szalardy L, etal., Neurodegener Dis. 2013 Feb 13.
Pubmed: (View Article at PubMed) PMID:23406886
DOI: Full-text: DOI:10.1159/000346267

Background: Deficient peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) 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-1alpha 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-1alpha protein (FL-PGC-1alpha) but expressing an N-truncated fragment. Methods: To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, alpha-synuclein, amyloid-beta, amyloid precursor protein, prion protein, FUS, TDP-43 and ubiquitin. Using hematoxylin and eosin, Kluver-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-1alpha 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-1alpha per se is insufficient to recapitulate major features of neurodegenerative diseases, but evokes a pathology seen in mitochondrial encephalopathies, which makes PGC-1alpha-deficient mice a valuable model for this yet incurable group of diseases.


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RGD Object Information
RGD ID: 7241824
Created: 2013-03-15
Species: All species
Last Modified: 2013-03-15
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.