About us
Research Interests
We are interested in the pathophysiology and experimental treatment of neurodegenerative disorders. We aim to identify mechanisms of selective neuronal vulnerability; and to validate the targets and mechanisms of action of small-molecule modulators of mitochondria, epigenetics and proteostasis.
Our primary focus is Huntington’s disease - a polyglutamine expansion disorder that preferentially kills medium spiny neurons in the striatum - but we are also interested in Parkinson’s disease and open to collaborations in the more general fields of neural and cell biology.
We have a broad interest in mitochondrial physiology and pharmacology, and in models organisms such as zebrafish - for pharmacology, ecotoxicology, and neurobiology studies.
Our main expertise includes functional imaging by live fluorescence videomicroscopy; molecular biology techniques; behavioural assays; experimental design and statistics.
Research Highlights
The interplay between mitochondria and proteostasis in Huntington’s disease
Abnormal proteostasis, dysfunctional mitochondria, and aberrant redox signalling are often associated in neurodegenerative disorders. We investigated how changes in redox signalling affect proteostasis mechanisms - including protein degradation pathways and unfolded protein responses - by testing the mitochondria-targeted antioxidant MitoQ in HD mice. We showed that abnormal redox signalling in muscle contributes to altered proteostasis and motor impairment, and that redox interventions can improve muscle performance, highlighting the importance of peripheral therapeutics in HD (Pinho et al 2020 Free Rad Biol Med 146:372-382).
Mitochondrial superoxide generation induces Parkinsonian phenotypes and Huntingtin aggregation
Superoxide generation by mitochondria is a major source of reactive oxygen species (ROS) which are capable of initiating redox signaling and oxidative damage. The current understanding of the role of mitochondrial ROS in health and disease has been limited by the lack of experimental strategies to selectively induce mitochondrial superoxide production. We performed a first in vivo study of the recently-developed mitochondria-targeted redox cycler MitoParaquat (MitoPQ) in the vertebrate zebrafish model and in a human cell model of Huntington's disease (HD). MitoPQ induced a parkinsonian phenotype in zebrafish, with decreased reflexes, spontaneous movement and dopaminergic neurodegeneration, without detectable effects on heart rate or atrioventricular coordination. In a HD cell model, MitoPQ promoted mutant huntingtin aggregation without increasing cell death. These results show that MitoPQ is a valuable tool for cellular and in vivo studies of the role of mitochondrial superoxide generation in redox biology, and as a trigger or co-stressor to model metabolic and neurodegenerative disease phenotypes (Pinho et al 2019 Free Rad Biol Med 130:318-327).
