Targeting mitochondria to treat rare and common neurodegenerative disorders

Mitochondrial dysfunction underlies the pathogenesis of a variety of human neurodegenerative diseases (NDs), either directly, as in the case of the rare Mitochondrial Diseases (MDs), or indirectly, as in more common NDs, such as Parkinson’s diseases. In particular a tight connection between vision and mitochondrial dysfunction has been extensively described. Several MDs are associated with some form of visual impairment. In particular Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), the most frequent mitochondrial optic neuropathies (ONs), are both characterized by degeneration of retinal ganglion cells and loss of vision. Interestingly, also the most common ONs, such as glaucoma and diabetic retinopathy also show signs of mitochondrial dysfunction and share clinical similarities with the hereditary MDs. Despite a vast amount of research these pathologies are still only treated symptomatically, and, in this respect, mitochondria could represent the common denominator and hence a promising therapeutic target. We recently demonstrated that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis function and clearance. We also show that these miRNAs are involved in the global regulation of mitochondrial turnover in the central nervous system (CNS) through the coordination of mitochondrial biogenesis and mitophagy. Interestingly miR-181a/b downregulation protects neurons from cell death and ameliorates the disease phenotype in different in vivo models of MDs, including LHON. 

The main interest of the lab is to develop and validate new therapeutic strategies enhancing mitochondrial turnover in the CNS to treat mitochondrial-associated neurodegeneration in a mutation-independent manner. Our strategies will be applied in models of rare diseases such as mitochondrial ONs, as well as in common disorders models such as glaucoma, Diabetic Retinopathy and Parkinson disease.

1. Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma. International Journal of Molecular Sciences, 2021
2. Mir-181a/B Downregulation Exerts a Protective Action on Mitochondrial Disease Models. EMBO Molecular Medicine, 2019
3. Synthetic Long Non-Coding Rnas [Sineups] Rescue Defective Gene Expression in Vivo. Scientific Reports, 2016
4. The Impairment of Hccs Leads to Mls Syndrome by Activating a Non-Canonical Cell Death Pathway in the Brain and Eyes. EMBO Molecular Medicine, 2013
5. Mutations in Cox7b Cause Microphthalmia with Linear Skin Lesions, an Unconventional Mitochondrial Disease. American Journal of Human Genetics, 2012

Complete List of Publications here