Focus on LRRK2 inhibition – implications for idiopathic Parkinson’s
Original article: LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease. Neurobiology of Disease: October 13, 2019
A new preclinical study has shown that LRRK2 inhibition in an animal model of Parkinson’s can improve lysosomal health and reduce alpha synuclein accumulation in dopaminergic neurons.
Why is it important?
It is an example of how insights gained from studying the effects of rare mutations in Parkinson’s can aid our understanding of the idiopathic disease process, and potentially discover drugs with wider benefits.
- Novelty 80% 80%
- Proximity 60% 60%
- Deliverability 70% 70%
This is an exciting new report because it suggests that ongoing LRRK2 inhibition clinical trials may have broader benefits for the Parkinson’s community than just those individuals affected by LRRK2 genetic variants. The biotech company Denali has just initiated a Phase Ib clinical study of their oral LRRK2 inhibitor and the Pharmaceutical company GlaxoSmithKline is exploring a LRRK2-focused clinical program. Caution is being taken as this is a novel class of experimental therapy and there could be potentially detrimental side effects. But these new preclinical results indicate that the approach is certainly worth exploring.
Mutations in the LRRK2 gene represent a rare but well-known type of Parkinson’,s affecting a small subset of people with Parkinson’s who carry this mutation. LRRK2 is involved in trafficking substances around the cell, and notably, in helping the cell clear waste products. It is involved with the function of lysosomes, which are small sacks with acidic contents which fuse with other sacks, endosomes, in order to degrade their cargo. LRRK2 overactivation has been shown to cause significant problems to neurons by impairing their ability to get rid of waste, including pathological alpha synuclein, the protein which misfolds and collects in cells thereby causing significant damage. But to what extent does this hold true for non-genetic forms of Parkinson’s? The Pittsburgh based group asked whether a LRRK2 inhibitor could prevent damage to lysosomes and reduce alpha synuclein accumulation in an animal model of Parkinson’s.
First, the group studied the effects of Parkinson’s in post-mortem tissue to chart its effect on lysosomes, using multiple markers, as well as alpha synuclein and dopaminergic loss. By studying the effects of the disease in human tissue, they then had a clear understanding of the effects they should try to recreate in the animal model. They then treated two groups of rats with rotenone, which is used as a pesticide, to create their animal model. They treated one group of animals for a period of between 9-14 days until significant signs of the disease were evident, but also treated another group for a shorter period of 5 days.
In the animals treated for up to 14 days, the researchers found evidence of significant dysfunction in terms of lysosome function and maturation, as well as alpha synuclein build up and dopaminergic degeneration similar to what they had observed in the post-mortem tissue. They also found evidence of early changes in lysosomes and alpha synuclein in the group that was treated for the short, 5-day period, which they termed the “pre-degenerative” group, although there was no neuronal loss yet.
Once they were certain that the animal model was successfully reproducing these problems, they then treated another group of animals with the LRRK2 inhibitor PF360 in parallel to giving rotenone, which would be responsible for causing damage to neurons. After the treatment period was over, the researchers found that compared to animals that had not been treated with PF360, those that had were showing a greater number of preserved lysosomes. Since their waste clearance mechanism was not as impaired, there was less alpha synuclein build up and less dopaminergic loss. In parallel to these markers, the group also studied GCAse. This is an enzyme whose function is compromised by GBA1 mutations, which represents another known genetic cause of Parkinson’s. Its function also appears linked to lysosomes, was affected by rotenone in these experiments, but this effect was prevented by the LRRK2 inhibitor.
Independent replication of these findings will first be necessary, before considering whether this approach should be prioritized for consideration in people. Crucial issues around safety and tolerability would be essential to establish first.
Where can I learn more?
Original article: Rocha, EM, De Miranda, BR, Castro, S, Drolet, R, Hatcher, NG, Yao, L, Smith, SM, Keeney, MT, Di Maio, R, Kofler, J, Hastings, TG, Greenamyre, JT. October 13, 2019. LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease.