Targeting Rab7 and TBC1D15 to overcome mitochondrial dysfunction in neurological diseases

Summary

Pharmacological manipulation of contacts between mitochondria and LE/Lys could provide opportunities to improve PD, CMT2B and NPC disease. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity to correct de-regulated MCS formation in several neurological pathologies. 
PhD Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.
Masters Opportunity
Yes. Prerequisite knowledge: Basic chemistry, biochemistry or related subjects. This project is an opportunity for students to discover the interplay of computational and synthetic chemistry, with molecular biology in a multidisciplinary research area. They will develop skills in the whole drug design process, from concept to delivery of a new drug candidate.


Supervisor(s)

Associate Professor Thomas Grewal , Professor Paul Groundwater, Professor David (Dai) Hibbs

Research Location

Sydney Pharmacy School

Program Type

Masters/PHD

Synopsis

De-regulated inter-organelle communication via membrane contact sites (MCS) between mitochondria and late endosomes/lysosomes (LE/Lys) compromise mitochondrial homeostasis (fission, fusion) and function in Parkinson's disease (PD), Charcot-Marie-Tooth type 2B (CMT2B) and Niemann-Pick Type C (NPC). Mechanistically, we and others showed that GTPase-activating protein (GAP) TBC1D15 -dependent Rab7 GTPase activity is critical for MCS formation in these diseases. Small molecules increasing Rab7/TBC1D15 complex formation could promote untethering of mitochondria-LE/Lys contacts to improve PD and CTM2B (carrying Rab7 mutations) pathophysiology. On the other hand, pharmacological inhibitors blocking Rab7/TBC1D15 complex formation could ameliorate improper cholesterol transfer to mitochondria in NPC1 mutants. Virtual screening of compound libraries will identify drug candidates that increase or inhibit Rab7/TBC1D15 complex formation to alter Rab7 GTPase activity, providing opportunities to correct de-regulated MCS formation in several neurological pathologies. The objectives are:
1. Molecular modelling and virtual screening of compound libraries to identify small molecules that reduce/increase Rab7-GTP levels through inhibition/promotion of Rab7/TBC1D15 complex formation.
2. To assess small molecule candidates for their ability to restore mitochondrial function in cell models for PD, CMT2B and NPC disease.

Additional Information

The molecular insights we gained from our previous work on NPC disease (1-3) are most relevant for mitochondrial dysfunction in PD and CMT2B, with TBC1D15-mediated Rab7-GTP hydrolysis being a critical molecular event in all these diseases (4,5). The supervisors of this multidisciplinary proposal have experience in drug design and testing (6) and internationally recognized expertise in cell metabolism and NPC disease (Supervisor A/Prof. T. Grewal) and molecular modelling, virtual screening and drug synthesis (Co-supervisors Prof. D. Hibbs and Prof. P. Groundwater). A collaborative network of internationally recognized researchers is also available for any technical advice and support throughout the duration of this proposal.
Further reading (Supervisors are in bold)
1. Cholesterol Overload: Contact Sites to the Rescue! Enrich C, Rentero C, Grewal T, Futter CE, Eden ER. Contact (Thousand Oaks). 2019 Jan 1;2:2515256419893507.
2. Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells. Meneses-Salas,...Grewal T...Cell Mol Life Sci 2020, 77:2839-57.
3. Lack of Annexin A6 Exacerbates Liver Dysfunction and Reduces Lifespan of Niemann-Pick Type C Protein-Deficient Mice. Meneses-Salas, ...Grewal T... Am J Pathol. 2021 Mar;191(3):475-486.
4. Kim et al. Nat Commun 2021 Mar 22;12(1):1807.
5. Wong et al. Dev Cell 2019 Aug 5;50(3):339-354.e4.
6. Identification of dual PPARα/γ agonists and their effects on lipid metabolism. Gao,...Grewal T, Groundwater PG, Hibbs DE. Bioorg Med Chem. 2015 Dec 15;23(24):7676-84.

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Keywords

Neurological diseases, Parkinson’s Disease (PD), Charcot-Marie-Tooth type 2B CMT2B), Niemann-Pick Type C (NPC), mitochondria, membrane contact sites, late endosomes/lysosomes, organelle communication, cholesterol, Rab7, TBC1D15, NPC1, Annexin A6

Opportunity ID

The opportunity ID for this research opportunity is: 2978

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