DiMaio

Research Focus
A deeper understanding of Parkinson’s disease (PD) pathogenesis is needed for effective treatments. PD is a complex age-related movement disorder, which includes many non-motor symptoms and affects seven to ten million people worldwide. In the United States, the number of PD cases per year is rapidly increasing and it is estimated that by the year 2040 this number will double. Thus, there is an urgent need for novel therapeutic approaches.

PD is a multifactorial disease caused by complex gene/environment interactions. The exact mechanism(s) of the selective nigrostriatal cell loss in PD are still poorly understood. However, there is strong evidence that indicates oxidative stress, aberrant LRRK2 kinase activity, -synuclein misfolding/aggregation, mitochondrial dysfunction and sustained neuroinflammation are key pathogenic features of PD.
There is a growing consensus that nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), a multi-subunit enzymatic complexes that generate reactive oxygen species may play a crucial role in PD-associated nigrostriatal degeneration. Several evidence of altered expression of NOX2 have been reported in the brain of PD patients, indicating that NOX2 may be an important pathogenic event and a potential target in PD therapy.
Dr. Di Maio is deeply committed to unraveling the intricate mechanisms underlying Parkinson's disease pathogenesis. His research centers on investigating oxidative stress-related events that contribute to the onset and progression of the disease. By employing innovative techniques and experimental strategies, he aims to generate knowledge and tools essential for developing new diagnostic and therapeutic approaches, with the goal of preventing or treating neurological disorders for the benefit of the broader community.
Recent studies, under Dr. Di Maio's leadership, unveil aberrant NOX2 activation in post-mortem substantia nigra from PD patients and PD animal models. This critical event is intricately connected with other key PD-related factors, such as aberrant LRRK2 kinase activity, α-synuclein modifications, mitochondrial dysfunction, and autophagy impairment. This reveals a feedforward cycle, underscoring NOX2's amplification signaling in PD pathogenesis. Importantly, the study provides the initial evidence of the relevance of neuronal NOX2 activity in idiopathic PD.
Expanding upon these discoveries, ongoing investigations are delving into a comprehensive understanding of the mechanistic details related to NOX2 downstream events. Furthermore, Dr. Di Maio's research is focused on delineating inventive therapeutic strategies involving the downregulation of NOX2 in the nigrostriatal pathway using antisense oligonucleotides. The research also aims to evaluate the potential beneficial effects of novel molecules with multitarget efficacy.

1. Horowitz M.P., Milanese C., Di Maio* R., Hu X., Montero L. M., Sanders L.H., Tapias, V., Burton E. A., Greenamyre J. T., and Mastroberardino P.G. (2011) Single- cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults. Antioxid. Redox Signal. Aug 15;15 (4):855-71. Jun 6. PMID: 21395478

2. Mullett S.J., Di Maio R, Greenamyre J.T. and Hinkle D.A. (2012) DJ-1 expression modulates astrocyte- mediated protection against neuronal oxidative stress. J. Mol. Neurosci. PMID: 23065353

3. Lee J.W., Tapias V, Di Maio R., Greenamyre J.T., Cannon J.R. (2014) Behavioral, neurochemical and pathologic alterations in bacterial artificial chromosome transgenic G2019S leucine-rich repeated kinase 2 rats. Neurobiol Aging. 2014 Jul 15. PMID: 25174649

4. Di Maio R., Barrett P.J., Hoffman E.K., Barrett C., Zharikov A., Borah A., H u X., McCoy J., C hu C.T., Burton E.A., Hastings .TG. and Greenamyre J.T., (2016) α-Synuclein bnds TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med. 2016 Jun 8;8(342):342ra78. doi: 10.1126/scitranslmed. aaf3634. PMID: 27280685

5. Di Maio R., Hoffman EK, Rocha EM, Keeney MT, Sanders LH, De Miranda BR, Zharikov A, Van Laar A, Stepan AF, Lanz TA, Kofler JK, Burton EA, Alessi DR, Hastings TG, Greenamyre JT. (2018) LRRK2 activation in idiopathic Parkinson's disease. Sci Transl Med. 2018 Jul 25;10(451). pii: eaar5429. doi: 10.1126/scitranslmed. aar 5429. PMID: 30045977

6. 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. (2020). LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson's disease. Neurobiol Dis. 2020 Feb; 134: 104626. doi: 10.1016/j.nbd.2019.104626. Epub 2019 Oct 13. PMID: 31618685

7. Van Laar VS, Chen J, Zharikov AD, Bai Q, Di Maio R, Dukes AA, Hastings TG, Watkins SC, Greenamyre JT, St Croix CM, Burton EA (2020). α-Synuclein amplifies cytoplasmic peroxide flux and oxidative stress provoked by mitochondrial inhibitors in CNS dopaminergic neurons in vivo. Redox Biol. Oct;37: 101695. doi: 10.1016/j. redox. 2020.101695. Epub 2020 Aug 22. PMID: 32905883

8. Keeney MT, Hoffman EK, Greenamyre TJ, Di Maio R (2021). Measurement of LRRK2 Kinase Activity by Proximity Ligation Assay. Bio Protoc. Sep 5;11(17): e4140. doi: 10.21769/ BioProtoc. 4140. eCollection 2021 Sep 5. PMID: 34604446 28.

9. Keeney M.T., Hoffman E.K., Farmer K., Bodle C.R., Fazzari M., Zharikov A., Castro S.L., Hu X., Mortimer A., Kofler J.K., Cifuentes-Pagano E., Pagano P.J., Burton E.A., Hastings T.G., Greenamyre J.T., Di Maio R. (2022). NADPH oxidase 2 activity in Parkinson's disease. S0969-9961(22)00146-2 DOI:

10. Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z, Sathyakumar S, Sarkar S, Jiang X, Dong X, Di Maio R, Wang W, Keeney MT, Felsky D, Sandoe J, Vahdatshoar A, Udeshi ND, Mani DR, Carr SA, Lindquist S, De Jager PL, Bartel DP, Myers CL, Greenamyre JT, Feany MB, Sunyaev SR, Chung CY, Khurana V. (2022). The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell. 2022 Jun 9;185(12):2035-2056.e33. doi: 10.1016/j. cell.2022. 05.008. PMID: 35688132

11. Di Maio R, Keeney MT, Cechova V, Mortimer A, Sekandari A, Rowart P, Greenamyre JT, Freeman BA, Fazzari M. (2023). Neuroprotective actions of a fatty acid nitroalkene in Parkinson's disease. NPJ Parkinson’s Dis. 2023 Apr 7;9(1):55. doi: 10.1038/s41531- 23-00502-3. PMID: 37029127