Biomarkers and tailored therapies for Parkinson’s disease

Charalampos Tzoulis is Professor of Neurology and Neurodegeneration and Consultant of Neurology at the University of Bergen and Haukeland University Hospital, Norway. He is the Director of the Neuromics Research Group, Head of Neurodegeneration Research and Vice Centre Director at the Neuro-SysMed Centre of Excellence for Clinical Research in Neurological Diseases.

During 2020, Professor Tzoulis’ group made keyadvances in their research projects: The NAD-PARK study, a phase-I randomized trial of NADsupplementation therapy with nicotinamide riboside (NR) in PD is completed and shows promising results, including conclusive evidence that NR penetrates the brain and impacts the cerebral metabolic profile.

The NO-PARK study, a phase-II randomized trial of NR in PD, is initiated in four out of seven centres and has already recruited nearly 100 patients. When completed, this study will provide a definite answer to whether NRtherapy can delay the progression of PD.

The STRAT-PARK initiative was also initiated in 2020. STRAT-PARK is a cohort study aiming to stratify PD according to clinical and biological variation, provide mechanistic insight into disease subtypes, and develop clinical biomarkers for patient stratification. So far, approximately 15 patients and controls have been recruited in Bergen, and the project is now starting at partner-centres in Trondheim and London Ontario, Canada.

The ParkOme initiative aims to map the multi-omic profile of PD at the individual and single-cell level. So far, the group has analyzed the genome, DNAmethylome, histone-acetylome (for selected markers), transcriptome, and proteome, for ~100 brain samples. In addition, they mapped the transcriptome in a total of ~1,000 brain samples. Analyses of the ParkOme data have generated novel insights into the genetics and gene-expression profile of PD. Moreover, in the first histone-acetylome-wide study in PD, the group showed that the brain of individuals with PD is characterized by a profound, genome-wide dysregulation of H3K27 acetylation and decoupling from transcription.

Single-cell transcriptomics, using the dedicated 10X-Chromium platform, are also well-underway. The methodology has been established and the data from the first pilot experiments in blood cells and nuclei from brain tissue are currently being analyzed. The group is also experimenting with the potential of long-read sequencing to map “obscure” areas of the genome, assess DNA-methylation natively, and evaluate RNAsplicing. The first samples have been analyzed and the group’s bioinformatics team is currently establishing the analyses pipelines.

Developing and testing mitochondrial therapies as well as biomarkers for patient selection is a central aim of the Neuro-SysMed work led by Professor Tzoulis. A detailed description of the ongoing and planned work can be found in the section for Parkinson’s disease.

Selected Key Publications

1. Haukeland University Hospital. NAD-PARK: A Double-blinded Randomized Pilot Trial of NAD-supplementation in Drug naïve Parkinson’s Disease [Internet]. clinicaltrials.gov; 2020 Feb. Report No.: NCT03816020. Available from: https://clinicaltrials. gov/ct2/show/NCT03816020
2. Haukeland University Hospital. A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson’s Disease: the NOPARK Study [Internet]. clinicaltrials.gov; 2020 Jun. Report No.: NCT03568968. Available from: https://clinicaltrials.gov/ct2/show/NCT03568968
3. Gaare JJ, Nido G, Dölle C, Sztromwasser P, Alves G, Tysnes O-B, et al. Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci. PLoS One. 2020;15:e0239824.
4. Nido GS, Dick F, Toker L, Petersen K, Alves G, Tysnes O-B, et al. Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition. Acta Neuropathol Commun. 2020;8:55.
5. Dick F, Nido GS, Alves GW, Tysnes O-B, Nilsen GH, Dölle C, et al. Differential transcript usage in the Parkinson’s disease brain. PLoS Genet [Internet]. 2020 [cited 2020 Nov 29];16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660910/
6. Dick F, Tysnes O-B, Alves GW, Nido GS, Tzoulis C. Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease. medRxiv. Cold Spring Harbor Laboratory Press; 2021;2021.03.18.21253875.
7. Toker L, Tran GT, Sundaresan J, Tysnes O-B, Alves G, Haugarvoll K, et al. Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain. bioRxiv. 2020;785550.
8. Gaare JJ, Nido GS, Sztromwasser P, Knappskog PM, Dahl O, Lund-Johansen M, Alves G, Tysnes OB, Johansson S, Haugarvoll K, Tzoulis C*. No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson’s disease. Brain. 2018 Jan 24.
9. Flønes I, Fernandez-Vizarra E, Lykouri M, Brakedal B, Skeie GO, Miletic H, Lilleng PK, Alves G, Tysnes OB, Haugarvoll H, Dölle C, Zeviani M and Tzoulis C*. Widespread neuronal complex I deficiency in Parkinson’s disease. Acta Neuropathol. 2017 Dec 21.
10. Nido G, Dölle C, Flønes I, Alves G, Tysnes OB, Haugarvoll H and Tzoulis C*. Ultra-deep mapping of neuronal mitochondrial deletions in Parkinson’s disease. Neurobiol Aging. 2017 Dec 8;63:120-127.
11. Brakedal B, Flønes I, Dölle C, Torkildsen Ø, Assmus J, Engeland A, Haugarvoll H and Tzoulis C*. Glitazone use associated with reduced risk of Parkinson’s disease. Movement Disorders, Mov Disord. 2017 Sep 1.
12. Dölle C, Flønes I, Nido G, Miletic H, Kristoffersen S, Lilleng KP, Larsen JP, Tysness OB, Haugarvoll K, Bindoff LA, and Tzoulis C*. Defective mitochondrial DNA homeostasis in the dopaminergic substantia nigra of patients with Parkinson’s disease. Nat Commun. 2016 Nov 22;7:13548.