Lack of age-related clinical progression in PGC-1α-deficient mice - implications for mitochondrial encephalopathies.

Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington's disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases.