By Andrew Czyzewski
Researchers have identified two molecules involved in mitochondrial function that appear to be important in the pathogenesis of Huntington's disease (HD).
In an HD mouse model, induction of the two targets virtually eliminated huntingtin protein aggregation and alleviated neurodegeneration, leading study co-author Albert La Spada (University of California, San Diego, USA) and colleagues to suggest that the molecules could be "attractive therapeutic targets."
HD is an autosomal dominant neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat within the first exon of the huntingtin (htt) gene. Misfolding of the disease protein is the crux of its molecular pathology affecting different neuronal populations.
Before the discovery of the htt gene, several lines of evidence implicated mitochondrial dysfunction in the disorder, with weight loss in patients and mouse models seen despite increased caloric intake, suggestive of a negative energy balance.
More recently, studies have demonstrated that mutant htt interferes with transcriptional programs coordinated by the peroxisome proliferator-activated receptor g (PPARg) coactivator 1a (PGC-1a), a regulator of mitochondrial biogenesis and oxidative stress.
La Spada et al determined whether genetic overexpression of PGC-1a could compensate for the documented interference with PGC-1a function in an HD mouse model. To do this, they established an inducible transgenic system for overexpressing PGC-1a.
The researchers found that not only did PGC-1a ameliorate HD neurologic phenotypes, but PGC-1a also virtually eradicated htt protein aggregates in the brains of HD mice.
It appears that PGC-1a's ability to activate the expression of reactive oxygen species (ROS) defense genes promotes ubiquitin-proteasome system (UPS) function, and this contributes to htt protein aggregate reduction, La Spada et al explain.
Further analysis demonstrated PGC-1a promoted htt turnover and the elimination of protein aggregates by activating transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway.
Notably they found that TFEB alone was capable of preventing htt aggregation even without PGC-1a induction - placing TFEB downstream of PGC-1a in the prevention of htt aggregation and neurotoxicity.
La Spada et al explain that "any process that disrupts mitochondrial function, either at the level of bioenergetics capacity or organelle/protein quality control, tends to preferentially compromise neurological function, resulting in neurodegeneration."
This is because neurons and other specialized central nervous system cells are unique in being postmitotic, having constant and high energy demands, and in needing to maintain protein quality control throughout a bipolar elongated cell body.
The say the findings "highlight the importance of PGC-1a function and TFEB action in neurodegenerative disease and establish PGC-1a and TFEB as attractive therapeutic targets for developing new therapies to treat HD and certain other neurodegenerative disorders characterized by protein misfolding."
The research is published in Science Translational Medicine.
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