Ciasca, G. | bioRxiv Science

bioRxiv2025

Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson's Disease and Alzheimer's Disease patients

BackgroundCombined metabolomic and HPLC-based analyses have identified significant metabolic alterations in serum and plasma amino acid levels of Parkinsons disease (PD) patients, underscoring their potential as biomarkers. However, it remains unclear whether these biochemical changes also manifest within the central nervous system or are confined to peripheral metabolism, reflecting systemic metabolic disturbances. MethodsTo address this issue, here we measured the levels of 44 different amino acids in post-mortem brain samples from MPTP-intoxicated, L-DOPA-treated monkeys and PD patients at different Braak Lewy body (LB) stages, compared to their respective controls, through targeted Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). ResultsIn MPTP-intoxicated monkeys, UPLC-MS revealed significant elevations in GABA, citrulline, threonine, isoleucine, phenylalanine, valine, glycine, and serine in the putamen, whereas we failed to detect alterations in the superior frontal gyrus (SFG). In PD patients, caudate-putamen (CPu) analysis demonstrated consistent serine upregulation across Braak LB stages 3-4 and 6, with stage 6 specifically showing additional proline increases and phosphoethanolamine decreases. Notably, serine was the sole amino acid significantly altered in both the putamen of MPTP-intoxicated monkeys and the CPu of PD patients. No significant amino acid alterations were observed in the SFG of PD patients, mirroring the findings in monkeys. In contrast, Alzheimers disease (AD) patient SFG samples showed significant increases in tryptophan, phenylalanine, threonine, tyrosine, and methionine relative to controls. ConclusionsThese findings demonstrate that cerebral amino acid alterations in PD are region-specific and primarily localized to brain areas receiving nigrostriatal dopaminergic innervation. Moreover, the cortical amino acid profile in AD differs substantially from that in PD, suggesting disease-specific metabolic signatures in distinct neurodegenerative conditions.

neuroscience↗

bioRxiv2019

Myelin Basic Protein dynamics from out-of-equilibrium functional state to degraded state in myelin

Living matter is a quasi-stationary out-of-equilibrium system; in this physical condition, structural fluctuations at nano- and meso-scales are needed to understand the physics behind its biological functionality. Myelin has a simple ultrastructure whose fluctuations show correlated disorder in its functional out-of-equilibrium state. However, there is no information on the relationship between this correlated disorder and the dynamics of the intrinsically disordered Myelin Basic Protein (MBP) which is expected to influence the membrane structure and overall functionality. In this work, we have investigated the role of this protein structural dynamics in the myelin ultrastructure fluctuations in and out-of-equilibrium conditions, by using synchrotron Scanning micro X Ray Diffraction and Small Angle X ray Scattering. We have induced the crossover from out-of-equilibrium functional state to in-equilibrium degeneration changing the pH far away from physiological condition. While the observed compression of the cytosolic layer thickness probes the unfolding of the P2 protein and of the cytoplasmic P0 domain (P0cyt), the intrinsic large MBP fluctuations preserve the cytosol structure also in the degraded state. Thus, the transition of myelin ultrastructure from correlated to uncorrelated disordered state, is significantly affected by the unfolding of the P2 and P0 proteins, which in this latter state do not act in synergistic manner with MBP to determine the membrane functionality.\n\nSTATEMENT OF SIGNIFICANCEA better comprehension of myelin degenerative process and the role of protein dynamics in this biological membrane is a topic issue in todays scientific community. The myelin ultrastructural fluctuations exhibit correlated disorder in its functional state, that becomes uncorrelated as it degenerates. In this work we elucidate the interplay of protein structural dynamics and myelin ultrastructure in the transition from its functional state to the degraded state. The results highlight that the intrinsically disordered Myelin Basic Protein (MBP) allows to preserve the myelin structure following both the small correlated fluctuations in physiological state and the large disordered fluctuations in degraded conditions, where the myelin functionality is close to being lost and the MBP remains the single active protein.

biophysics↗