Our Science

neuron receptor

Discovering a Key Driver of Parkinson’s Disease

Parkinson’s disease (PD) is characterized by the dysfunction and death of dopamine-producing neurons, leading to movement irregularities. Both genetic and environmental factors contribute to PD, with idiopathic PD (iPD) making up ~90% of cases1. While the exact causes of Parkinson’s disease are not fully understood, research has identified several malfunctioning cellular processes in PD, including α-synuclein aggregation, LRRK2 kinase hyperactivity, mitochondrial dysfunction, neuroinflammation, and disrupted calcium homeostasis2. In collaboration with Professor Tim Greenamyre, MD, PhD, a Robert Pritzker Prize-winning researcher from the University of Pittsburgh, Acurex has made significant strides in understanding these mechanisms.

4-HNE is a toxic by-product of lipid peroxidation that is strongly elevated in PD and correlated with PD progression3-5. Our research indicates that lipid peroxidation, which produces 4-HNE, is sufficient to induce LRRK2 kinase hyperactivity*. Additionally, LRRK2 is required for lipid peroxidation related to Parkinson’s disease suggesting an important feedback loop6. Further, aberrant 4-HNE appears to be a driving factor in both idiopathic PD and Parkinson’s disease related to genetic mutations of LRRK2. Importantly, Acurex has shown that 4-HNE is primarily produced through the enzyme 15-lipoxygenase (15-LO), rather than as a result of non-specific oxidative stress as previously assumed by many. Through inhibiting 15-LO, Acurex’s lead drug candidate, CU-13001, prevents 4-HNE production, LRRK2 hyperactivation, and downstream pathologies like α-synuclein aggregation and mitochondrial dysfunction. By acting upstream of previously well-studied pathways, our targeted therapeutics are aimed at treating what could be a key underlying cause of PD, aiming to improve patients’ quality of life.

Parkinson’s affects more than 10 million people worldwide16. PD progresses gradually over years or decades, with symptoms that worsen over time, and there are no drugs that slow or stop the disease’s progression.

Miro1 Biomarker

Acurex has developed a novel biomarker for PD based on an initial discovery at Stanford University involving the protein Miro17,8. This biomarker serves as a tool for measuring mitochondrial dysfunction, a hallmark of PD and many other age-related diseases. The biomarker has shown robust results in tests involving over 200 PD patients. 

Acurex is finalizing the development of an ELISA-based Miro1 test using proprietary monoclonal antibodies. We believe that this test can improve the detection and progression of Parkinson’s disease. Acurex also believes that by measuring this biomarker in the blood of Parkinson’s disease patients, specifically in peripheral blood mononuclear cells (PBMCs), it may be possible to detect early biochemical evidence of disease modification in clinical trials.

doctor talking to patient

Mitophagy Dysfunction Drug Discovery (M3D) Platform

Acurex uses its high-throughput Mitophagy Dysfunction Drug Discovery (M3D) platform to identify drug targets. Mitochondrial dysfunction and the process of recycling damaged mitochondria (mitophagy) play an early and important role in the development of many diseases, such as Parkinson’s disease9-15.

Acurex’s drug discovery approach uses the phenotypic screening of Miro1 status to pinpoint specific signaling pathways driving mitophagy defects. Acurex’s M3D platform has identified drug targets that can reverse or improve mitophagy dysfunction across different genetic backgrounds and cell types in individuals with PD. The M3D platform can be utilized for various diseases and cell types, enabling drug discovery in multiple mitochondrial disease areas.

lab machine

References

  1. Pang, S. Y. Y. et al. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease. Translational Neurodegeneration vol. 8 https://doi.org/10.1186/s40035-019-0165-9 (2019).
  2. Dong-Chen, X., Yong, C., Yang, X., Chen-Yu, S. T. & Li-Hua, P. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduction and Targeted Therapy vol. 8 https://doi.org/10.1038/s41392-023-01353-3 (2023).
  3. Yoritaka, A., Hattori, N., Uchidat, K., Tanaka, M. & Stadtmani, E. R. Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. 93, 2696–2701 https://doi.org/10.1073/pnas.93.7.2696 (1996).
  4. Selley, M. L. (E)-4-hydroxy-2-nonenal may be involved in the pathogenesis of Parkinson’s disease. Free Radic Biol Med 25, 169–74 https://doi.org/10.1016/s0891-5849(98)00021-5 (1998).
  5. Fedorova, T. N. et al. Lipid Peroxidation Products in the Blood Plasma of Patients with Parkinson’s Disease as Possible Biomarkers of Different Stages of the Disease. Neurochemical Journal 13, 391–395 https://doi.org/10.1134/S1819712419040020 (2019).
  6. Keeney, M. T. et al. LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson’s disease. Sci Transl Med 16, 17–20 https://doi.org/10.1126/scitranslmed.adl3438 (2024).
  7. Hsieh, C.-H. H. et al. Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson’s Disease. Cell Stem Cell 19, 709–724 https://doi.org/10.1016/j.stem.2016.08.002 (2016).
  8. Shaltouki, A., Hsieh, C.-H. H., Kim, M. J. & Wang, X. Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson’s models. Acta Neuropathol 136, 607–620 https://doi.org/10.1007/s00401-018-1873-4 (2018).
  9. Wang, X.-L. et al. Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson’s Disease. Cell Mol Neurobiol (2021) https://doi.org/10.1007/s10571-021-01039-w.
  10. Palikaras, K., Lionaki, E. & Tavernarakis, N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20, 1013–1022 https://doi.org/10.1038/s41556-018-0176-2 (2018).
  11. Xiao, B., Kuruvilla, J. & Tan, E.-K. Mitophagy and reactive oxygen species interplay in Parkinson’s disease. NPJ Parkinsons Dis 8, 135 https://doi.org/10.1038/s41531-022-00402-y (2022).
  12. Imberechts, D. et al. DJ-1 is an essential downstream mediator in PINK1/parkin-dependent mitophagy. Brain (2022) https://doi.org/10.1093/brain/awac313.
  13. Soutar, M. P. M. et al. Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci. Brain 145, 4349–4367 https://doi.org/10.1093/brain/awac325 (2022).
  14. Liu, J., Liu, W., Li, R. & Yang, H. Mitophagy in parkinson’s disease: From pathogenesis to treatment. Cells vol. 8 https://doi.org/10.3390/cells8070712 (2019).
  15. Wang, S. et al. The mitophagy pathway and its implications in human diseases. Signal Transduct Target Ther 8, 304 https://doi.org/10.1038/s41392-023-01503-7 (2023).
  16. Pringsheim, T. et al. The prevalence of Parkinson’s disease: A systematic review and meta-analysis. Mov Disord, 29, 1583-90 https://doi.org/10.1002/mds.25945 (2014).

*Unpublished data