Research reportLack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies
Introduction
Impaired mitochondrial function has widely been linked to the development of various neurodegenerative disorders, including Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) [1], [2], [3], [4]. These disorders are characterized by a relatively selective loss of neurons in different central nervous system (CNS) areas, corresponding to the leading clinical manifestations, in most of them with specific motor impairments. In addition, alterations of either nuclear or mitochondrial genome affecting mitochondrial functions at various levels are pathognomonic of a group of congenital multi-systemic diseases, collectively termed mitochondrial encephalopathies [5], [6], [7], [8]. These diseases that include Kearns-Sayre syndrome (KSS), Leigh syndrome (LS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neuropathy, ataxia, retinitis pigmentosa (NARP), and mitochondrial neurogastrointestinal encephalopathy (MNGIE) generally present with a progressive symptomatology corresponding to the multi-systemic involvement of the brain, skeletal muscles, heart, and liver, among other less commonly affected organs [5], [6], [7], [8]. The involvement of the brain manifests in different forms of mitochondrial encephalopathy in the different syndromes, commonly characterized by various extents of white matter vacuolation accompanied by reactive astrogliosis with or without apparent selective neurodegeneration in particular brain regions.
Several lines of evidence indicate that peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator 1-alpha (PGC-1α), a nuclear-encoded coactivator of an armada of transcriptional factors that play extensive roles in the activation of adaptive mitochondrial responses, may contribute to the mitochondrial dysfunction in neurodegenerative disorders, including PD, AD, HD, and ALS [1], [2], [3], [4]. The coactivation of genes such as nuclear respiratory factor 1 and 2 (NRF-1, -2), estrogen-related receptors (ERRs), myocyte-specific enhancer factor 2C (MEF2C), and PPARs results in an enhanced expression of a wide spectrum of proteins involved in mitochondrial function and biogenesis [9], including mitochondrial replication and transcription, the import and assembly of respiratory complex subunits, a tissue-dependent induction of oxidative phosphorylation and thermoregulation, the enhancement of gluconeogenesis and fatty acid oxidation, as well as the increase of defense against oxidative stress [10], [11]. In line with these, experimental evidence suggests that pharmacological or transcriptional activation of PGC-1α may hold therapeutic value in neurodegenerative as well as mitochondrial diseases [11], [12], [13].
Despite its broad roles in mitochondrial functions, the absence of PGC-1α is compatible with life. The first pioneering publications with two independent murine PGC-1α knockout strains commonly described signs of striatal degeneration, proposing that these animals might model HD [14], [15], which corresponded with the findings of reduced striatal expression of PGC-1α and its target genes in the striatum of HD patients [16], [17] as well as in its transgenic in vivo [16], [17], [18] and in vitro models [16], [17] (comprehensively reviewed in [11]). Not doubting the potentially essential role of PGC-1α dysfunction in the pathogenesis of HD, the concept that PGC-1α-deficient animals themselves might model HD, however, has recently been questioned by serial findings of independent morphological and molecular biological analyses [19], [20], [21]. One of the two pioneering publications reported the development of a complete (i.e., with no residual expression) PGC-1α whole-body knockout strain, exhibiting hyperactivity with no overt muscle phenotype [14]. Though PGC-1α has recently been demonstrated to have a number of previously unknown isoforms [22], to the current knowledge, this strain can still be regarded as a complete knockout of PGC-1α [23]. Contrastingly, the second pioneering publication reported the development of another whole-body knockout strain demonstrating hypomotility and weakness [15], a strain later turned out to express an N-terminal fragment of PGC-1α (NT-254, functionally identical with the 267 amino acid-long N-truncated splice variant, NT-PGC-1α) but not the full-length protein (FL-PGC-1α) [24]. This was then followed by reports on muscle-specific complete PGC-1α knockouts with myopathic signs and weakness [25], as well as on complete whole-body and brain-specific PGC-1α knockouts failing to recapitulate hyperactive behavior [20], [26] but demonstrating impaired coordination [20] and ataxia proposed to be of cerebellar type [27]. Notably, the increasing behavioral data from the complete knockout phenotypes tend to delineate a phenotype resembling a relatively compensated mitochondrial disease. Correspondingly, recent neuropathological analyses on FL-PGC-1α -/- mice reported wide-spread, locally dramatic vacuolation of the white matter, predominantly affecting the thalamus, basal ganglia, internal capsule, pontomedullary brainstem as well as the cerebellum, accompanied by reactive astrogliosis in the brainstem and cerebellar nuclei [19]. In fact, this pathology is highly reminiscent of that seen in a human mitochondrial spongiform encephalopathy, with particular resemblance to KSS [21]. Notably, no morphological correlates of striatal axonal or neuronal degeneration were apparent in FL-PGC-1α -/- animals [19] even at 75 weeks of age [21], which corresponds with earlier findings on young (postnatal day 10) FL-PGC-1α -/- animals via immunohistochemistry of striatal neurofilament [28] and has recently been confirmed by Lucas et al. demonstrating no significant loss of medium-sized spiny neurons via molecular biological methods in complete PGC-1α -/- mice [20]. Of note, the same group reported their observation of a relatively stable phenotype in complete PGC-1α -/- mice, with no robust progression between 4 and 12 weeks of age [20].
All these above detailed contradictory findings on PGC-1α-deficient mice and the recent report of a relatively stable phenotype in young PGC-1α -/- animals prompted us to perform a comprehensive profiling of motor phenotype of FL-PGC-1α -/- mice bred in our institute through a wide spectrum of age, with a special focus on the issue of phenotypic progression. The manuscript also addresses the expression profile of novel CNS-specific isoforms of PGC-1α in FL-PGC-1α -/- mice (containing exon B4) [29], a feature previously not characterized in this strain. As a supplement of prior published neuropathological findings on adult [19] and aged [21] FL-PGC-1α -/- brains, additional neuropathological work-up has been performed to better understand the potential background of the observed phenotypic alterations, including histopathological analysis of the retina, spinal cord, and skeletal muscle.
Section snippets
Animals
The study enrolled male FL-PGC-1α -/- (n = 20–24) and C57Bl/6J wild-type (n = 22–26) [15]. The animals were housed in cages (maximum 4 per cage) in standard conditions with 12–12 h light-dark cycle and ad libitum access to standard pellet food and water. The experiments were performed in accordance with the European Communities Council Directive (86/609/EEC) and were approved by the local Animal Care Committee. The study animals were randomized from a population ranging through a wide spectrum of
Behavioral analysis
FL-PGC-1α -/- animals demonstrated remarkably poorer performance on the inverted screen compared to their wild-type counterparts with significantly shorter latency to fall from the grid (p = 0.001; 33.5 s [15.25 s–84.25 s] vs 99.5 s [51.0 s–231.75 s]; Fig. 1A). The worse performance of FL-PGC-1α -/- animals was not attributable to an increased body weight, contrastingly, FL-PGC-1α -/- animals showed a tendency towards decreased body weight compared to controls (p = 0.076; 27.70 g [26.17 g–28.63 g] vs 28.31
Discussion
Recent neuropathological analyses on FL-PGC-1α-deficient mice revealed a pathology highly reminiscent of KSS [19] even at the ultrastructural level [21], suggesting that PGC-1α-deficient murine strains might serve as models for mitochondrial diseases. However, based predominantly on vacuolation and astrogliosis reported in the striatum, former studies on the complete PGC-1α as well as the FL-PGC-1α whole-body knockout strains had proposed that PGC-1α-deficient mice could be regarded as models
Conclusion
We conclude that FL-PGC1α -/- animals and the applied behavioral assessment techniques can be suitable for pharmacobehavioral studies with a therapeutic aim in mitochondrial encephalopathies, as they exhibit several clinical and neuropathological phenotypic hallmarks of such diseases. This is of importance because of the paucity of viable animal models that exhibit both morphological and behavioral symptoms of a mitochondrial disease. An important limitation revealed, however, in our study is
Acknowledgements
The study was supported by the Hungarian Brain Research Program – Grant No. KTIA_13_NAP-A-II/18., the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Program’, TÁMOP-4.2.2/B-10/1-2010-0012, and TÁMOP-4.2.2.A-11/1/KONV-2012-0052. Denes Zadori was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
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