Study Rationale:
Disruption of 14-3-3 proteins is implicated in PD, and we have previously demonstrated that increasing 14-3-3 expression is protective in PD models. Recently, we observed that 14-3-3 phosphorylation — a chemical modification that affects normal function — is increased in PD brains compared to controls. This modification reduces neuroprotection by 14-3-3s in PD models. In this study, we will confirm our initial findings with an independent PD sample group and test the specificity of this increased 14-3-3 phosphorylation to PD compared to other neurodegenerative diseases.
Hypothesis:
We hypothesize that phosphorylation of 14-3-3s contributes to the neurodegenerative process in PD and that it may serve as a potential biomarker for PD.
Study Design:
We will measure 14-3-3 phosphorylation levels in the temporal cortex from PD patients and from patients with Alzheimer’s disease, with progressive supranuclear palsy or with dementia with lewy bodies. By comparing PD patients to patients with other neurodegenerative illness, we will be able to determine if the 14-3-3 changes are specific to PD. In addition, we will test whether phosphorylation of 14-3-3 proteins is detectable in the serum or cerebrospinal fluid of patients.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If our results are promising, this would suggest that 14-3-3 phosphorylation may serve as a biomarker for diagnosis and/or disease progression of PD. A biomarker would help in early diagnosis and faster testing of potential therapies.
Next Steps for Development:
If we find that increased 14-3-3 phosphorylation is specific to PD, future studies would further pursue whether this increased 14-3-3 phosphorylation is detectable in serum and/or cerebrospinal fluid of patients with PD.
Final Outcome
The goal of our project is to test whether 14-3-3 phosphorylation is a potential biomarker for Parkinson’s disease (PD). 14-3-3 phosphorylation is a chemical modification that can regulate the normal function of 14-3-3 proteins. We have evaluated three phosphorylation sites, serine 232 (S232), serine 58 (S58), and serine 184 (S184), in 150 human brains from several different neurodegenerative disorders. We have evaluated 25 brains each from control, PD, Dementia with Lewy Bodies (DLB), Alzheimer’s disease (AD), Alzheimer’s disease with Lewy Bodies (AD-LB), and Progressive Supranuclear Palsy (PSP) patients. Temporal cortex tissue from all brains were separated into detergent soluble and insoluble fractions. With regard to the S232 phosphorylation site, we observed statistically significant decreases in S232 phosphorylation in the soluble fractions of DLB, AD, and AD-DLB brains and a similar trend in PD brains. We saw a converse increase in S232 phosphorylation in the insoluble fractions from PD, DLB, AD, and AD-DLB brains. The greatest changes with regard to S232 phosphorylation were noted in AD brains, and DLB brains showed greater decline compared to PD brains. This relative difference between PD and DLB is consistent with the fact that more alpha-synuclein pathology is generally present in DLB compared to PD in the temporal cortex. S58 phosphorylation was statistically increased in the soluble fractions of AD-LB brains, and a trend towards increased S58 phosphorylation in the soluble fractions of AD and DLB brains. S184 phosphorylation was increased in DLB brains but not in the other disorders.
Our data show that 14-3-3 phosphorylation is a marker of neurodegeneration: we observed alterations in 14-3-3 phosphorylation in several neurodegenerative disorders. However, the diseases differ in which phosphorylation sites are altered – we term this as a “14-3-3 phosphorylation signature.” PD is marked by altered S232 phosphorylation only. AD is marked by changes in both S58 and S232. DLB is marked by changes in S58 and S184. PSP shows no changes in any 14-3-3 phosphorylation sites. We propose the “14-3-3 phosphorylation signature” could serve to distinguish different neurodegenerative disorders.
Publications
Slone SR, Lavalley N, McFerrin M, Wang B, Yacoubian TA. Alterations in 14-3-3 phosphorylation observed in Parkinson’s disease affect neuroprotective potential of 14-3-3 proteins, Neurobiol Dis. 2015; 79:1-13.