A convergent metabolic-kinase signaling axis links Parkinson s disease and multiple system atrophy

Velasquez, E.; Savchenko, E.; Toledo, A. G.; Nasstrom, E.; Johansson, A.; Colini Baldeschi, A.; Lunnon, K.; Deierborg, T.; Pomeshchik, Y.; Rezeli, M.; roybon, l.

doi:10.64898/2026.06.11.731777

bioRxiv · 10.64898/2026.06.11.731777

A convergent metabolic-kinase signaling axis links Parkinson s disease and multiple system atrophy

Velasquez, E.·Savchenko, E.·Toledo, A. G.·Nasstrom, E.·Johansson, A.·Colini Baldeschi, A.·Lunnon, K.·Deierborg, T.·Pomeshchik, Y.·Rezeli, M.·roybon, l.

View original source ↗Export metadata ↓

Abstract

Parkinsons disease (PD) and multiple system atrophy (MSA) are alpha-synucleinopathies with overlapping clinical phenotypes but distinct cellular pathological hallmarks. Whether these disorders share upstream molecular changes beyond alpha-synuclein aggregation remains unresolved. Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain spheroids containing dopaminergic neurons from individuals with monogenic PD, idiopathic PD, MSA, and controls, and applied integrated proteomics, metabolomics, and phosphoproteomics to define disease-associated biochemical programs and their regulatory architecture. Despite their distinct etiologies, PD and MSA spheroids displayed highly concordant molecular remodeling, with cellular metabolism emerging as the dominant shared disturbance. Network analyses identified coordinated changes in central carbon metabolism, oxidative phosphorylation, branched-chain amino acid catabolism, pantothenate/CoA metabolism, and lipid remodeling, coupled to phosphorylation-driven rewiring of MAPK, mTOR, AMPK, PKA/PKC, and second-messenger kinase programs. Importantly, these metabolic and signaling axes were also prominent in postmortem substantia nigra from PD and MSA donors, supporting conservation between patient-derived models and postmortem brain tissue. Together, these data identify metabolic dysregulation as a unifying molecular feature across PD and MSA and suggesting phosphorylation-linked metabolic control nodes as candidate entry points for therapeutic intervention. HighlightsO_LIPD and MSA exhibit molecular programs that extend beyond alpha-synuclein pathology. C_LIO_LIProteomics identifies metabolism as the dominant shared disease axis across PD and MSA. C_LIO_LIMetabolomics resolves a coupled glucose-TCA-BCAA-CoA-lipid remodeling program in PD and MSA. C_LIO_LIPhosphorylation-centered kinase networks link signaling rewiring to metabolic bottlenecks. C_LIO_LIShared metabolic features are conserved between patient iPSC-derived midbrain spheroids and substantia nigra. C_LI Graphic abstract (generated using BioRender) O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/731777v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1748e51org.highwire.dtl.DTLVardef@12b8f91org.highwire.dtl.DTLVardef@de8893org.highwire.dtl.DTLVardef@1d89ea1_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Velasquez, E., Savchenko, E., Toledo, A. G., Nasstrom, E., Johansson, A., Colini Baldeschi, A., Lunnon, K., Deierborg, T., Pomeshchik, Y., Rezeli, M., roybon, l.. 2026-06-16. A convergent metabolic-kinase signaling axis links Parkinson s disease and multiple system atrophy. https://doi.org/10.64898/2026.06.11.731777

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗

bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗