Parkinson's Disease & Dystonia

Movement Disorders — An Integrated Research Program

My work centers on the molecular and cellular biology of Parkinson's disease — α-synuclein pathology, lysosomal dysfunction, dopaminergic neuron vulnerability, and neuroinflammation — built on iPSC-derived human neuron platforms, CRISPR-edited disease lines, and quantitative multi-modal readouts. The same platform translates directly to dystonia and other basal-ganglia / motor-circuit disorders: iPSC differentiation into dopaminergic and cortical/striatal-projecting neurons, microelectrode-array (MEA) electrophysiology, calcium imaging, high-content confocal and electron microscopy, CRISPR knockout modeling, and mass-spectrometry proteomics. This page consolidates the core figures, assays, and findings from across the site that are directly relevant to evaluating my capabilities in Parkinson's disease and dystonia.

Research Pillars

• iPSC-derived midbrain dopaminergic & cortical neurons
• α-Synuclein PFF seeding & dual-hit Lewy-body modeling
• CRISPR-edited disease lines (LRRK2, GBA, Parkin, SNCA)
• Lysosomal dysfunction & membrane permeabilization
• Neuroinflammation (IFN-γ, TNF-α, IL-1β) and microglial co-culture
• MEA electrophysiology & calcium imaging — circuit-level readouts for movement disorders
• Parkin-agonist & lysosomal-rescue small-molecule discovery
• Biomarker development: pS129, LAMP1/2, TFEB, NfL, HDAC6

Basal Ganglia Circuitry — PD vs Dystonia (Interactive)

The basal ganglia organize voluntary movement through the balance of a direct (movement-promoting) and an indirect (movement-inhibiting) pathway, modulated by dopamine from the substantia nigra pars compacta (SNc) and a fast-stop hyperdirect projection from motor cortex to the subthalamic nucleus (STN). Parkinson’s disease and dystonia are both classical basal-ganglia disorders yet produce opposite motor phenotypes — hypokinetic bradykinesia/rigidity/tremor versus hyperkinetic, sustained agonist–antagonist co-contraction. Click a state below to visualize pathway-specific dysfunction.

Human iPSC Dopaminergic & Cortical Neuron Models

I have generated and banked over 20 iPSC lines, including nine patient/donor lines used for modeling Parkinson's disease pathology. Differentiation spans midbrain dopaminergic neurons (for PD modeling), cortical / excitatory neurons (for circuit studies relevant to both PD cognitive features and dystonia motor-cortex biology), astrocytes, and microglia-like cells for co-culture. Cell identity is confirmed by immunocytochemistry (TH, DAT, GIRK2, Neurofilament, TUJ1, MAP2), HPLC quantification of dopamine and metabolites, and MEA electrophysiology for spontaneous firing patterns and waveform analysis.

Identity & Quality Control

• TH+ midbrain dopaminergic neurons (DAT, GIRK2, Neurofilament co-stain)
• Cortical excitatory neurons (TUJ1, MAP2, VGLUT1)
• HPLC dopamine & DOPAC quantification
• MEA spontaneous activity & spike waveform analysis
• Calcium imaging (Fluo-4) of spontaneous transients
• Karyotyping, pluripotency panel, colony QC

Fig. iPSC-derived DA neuron identity — DAT, GIRK2, Neurofilament, and TH co-expression

Fig. MEA raster & waveforms — spontaneous firing across an iPSC-DA network

Fig. Fluo-4 calcium imaging — spontaneous transients in iPSC-DA neurons

Relevance to Dystonia

The same iPSC differentiation, MEA, and calcium-imaging pipelines are directly applicable to dystonia modeling — circuit-level firing-pattern abnormalities, paroxysmal burst activity, and co-contraction-like synchrony phenotypes are quantifiable on our MEA platform, and patient-derived lines carrying movement-disorder alleles (e.g., TOR1A/DYT1, GNAL, THAP1, KMT2B) can be differentiated into cortical and striatal-adjacent neurons for comparative electrophysiology and morphology. Where direct PD data is shown below, the underlying methodology — from differentiation to high-content imaging to CRISPR perturbation — transfers to dystonia models with minimal adaptation.

α-Synuclein Biology, PFF Seeding, & Lewy-like Inclusions

Sonicated recombinant α-synuclein preformed fibrils (PFFs) seed endogenous α-synuclein aggregation in iPSC-DA neurons. Fibrils are internalized primarily by RAC1-dependent macropinocytosis, bypass early endosomes, and reach lysosomes within two minutes of addition. Seeds recruit endogenous α-synuclein and template the formation of pS129-positive, Thioflavin-S-positive Lewy-like inclusions over 14–21 days. A dual-hit paradigm (PFF + IFN-γ) dramatically accelerates inclusion formation and models the inflammatory context of sporadic PD.

Fig. Dual-hit Parkinson's model — PFFs + cytokine challenge → lysosomal dysfunction → Lewy-like pathology

Pharmacodynamic Biomarker Panel

Multi-target panel quantifying α-synuclein (pS129 & total), lysosomal proteins (LAMP1/LAMP2), autophagy flux (LC3B, p62), transcriptional regulation (TFEB), and aggresome machinery (HDAC6) across vehicle, dual-hit, and rescue conditions.

Inclusion Growth Over Time

Time-resolved phospho-synuclein (pSyn) inclusion growth in TH+ dopaminergic neurons exposed to PFF + IFN-γ over 7, 10, and 14 days. Deconvoluted panels with size measurements (µm) show progressive inclusion maturation and coalescence, providing quantitative morphometric data to benchmark therapeutic rescue.

Fig. pS129 α-synuclein inclusion growth — deconvoluted morphometry at 7, 10, and 14 days post dual-hit

Orthogonal Antibody Validation

Confocal time course of α-synuclein-HA expressing neurons probed with two independent phospho-synuclein antibodies (phospho S129 and pSyn#64). Control neurons show diffuse cytoplasmic α-syn-HA signal; IFN-γ–treated neurons develop perinuclear pS129-positive inclusions by day 7 that mature through day 14 — validating the biomarker with orthogonal antibody approaches.

Fig. Phospho-synuclein biomarker validation — dual antibody time course (pS129 & pSyn#64)

Biochemical Isolation of Inclusions

Sequential extraction and subcellular fractionation reveal enrichment of α-synuclein and HDAC6 (aggresome marker) in the insoluble pellet under dual-hit conditions, biochemically confirming the confocal pathology.

Fig. Sequential extraction — α-synuclein & HDAC6 enrichment in the insoluble pellet under dual-hit

Lysosomal Dysfunction, GBA & Fibril Trafficking

Lysosomal biology sits at the center of Parkinson's disease pathogenesis — and is increasingly implicated in movement-disorder biology more broadly. I developed a custom nanogold-PFF conjugation protocol, published in STAR Protocols (first author), that permits direct electron-microscopic visualization of fibril trafficking from the cell surface into lysosomes. Live-cell confocal (LysoTracker / LysoSensor) quantifies lysosomal number and pH; galectin-3 puncta report membrane permeabilization; and GBA-knockout iPSC neurons reveal heightened vulnerability to fibril-induced inclusions.

Fig. Nanogold-PFF EM — surface → macropinosome → lysosome trafficking

Fig. Galectin-3 puncta — PFF-induced lysosomal membrane permeabilization

Fig. EM — α-synuclein fibrils within ruptured lysosomes

Fig. GBA KO — enlarged LAMP1+ lysosomes with accumulated PFF-488

Western Blot Pharmacodynamic Panel

Multi-target Western blot across U2OS, U87, and SH-SY5Y cell lines under control, IFN-γ, PFF, and dual-hit conditions quantifies CHC (clathrin heavy chain), LAMP1, LAMP2, NRF2, TFEB, and α-synuclein in a single readout — capturing endocytic machinery, lysosomal integrity, oxidative stress, and aggregation state.

Fig. Pharmacodynamic Western — CHC, LAMP1, LAMP2, NRF2, TFEB, α-synuclein across cell lines

CRISPR-Edited iPSC Lines for PD & Movement-Disorder Biology

I have generated CRISPR-edited iPSC lines targeting major Parkinson's disease genes to dissect protein function and model familial forms of disease. The same workflow — ribonucleoprotein delivery, clonal isolation, Sanger/amplicon-seq validation, karyotype confirmation, and rigorous QC — applies directly to dystonia-associated loci (e.g., TOR1A, GNAL, THAP1, KMT2B) for patient-mimetic and isogenic-knockout comparisons.

Parkinson's-Relevant Knockouts Generated

• SNCA KO — abolishes PFF-templated pathology entirely; critical control for endogenous recruitment
• GBA KO — heightened fibril vulnerability, enlarged LAMP1 lysosomes, Gaucher-disease–adjacent model
• LRRK2 KO — altered endolysosomal trafficking; platform for kinase-inhibitor pharmacology
• Parkin (PRKN) KO — impaired mitophagy; screen platform for Parkin-agonist rescue

Fig. iPSC synucleinopathy platform — CRISPR-edited lines & downstream pathology readouts

Viral Transduction & Expression

Adenoviral and lentiviral systems enable rapid overexpression, knockdown, and tagged α-synuclein expression (e.g., α-syn-HA) for live tracking of endogenous vs. seed-templated aggregation.

Fig. Adenoviral α-syn-HA + IFN-γ — pSyn S129 accumulation confirms endogenous recruitment

Cytokine Signaling, Microglia, & Dopaminergic Vulnerability

Neuroinflammation is a core driver in both familial and sporadic Parkinson's disease. Systematic dissection of IFN-γ, TNF-α, and IL-1β signaling on iPSC-DA neurons reveals MHC-I upregulation, antigen-presentation machinery activation, and downstream lysosomal dysfunction. In dual-hit conditions, TNF-α and IL-1β act synergistically with PFF seeding to accelerate α-synuclein phosphorylation and Lewy-like inclusion formation (4.2× increase vs PFF alone). Receptor-level biomarker imaging (IFNGR1, IFNGR2, TNFR2, IL1R1) confirms surface expression and co-localization with PFF aggregates on neuronal processes.

Fig. IFNGR1 & IFNGR2 receptor expression — multichannel confocal with PFF488 co-localization

Neuron–Glia Co-Culture

iPSC-derived microglia (IBA1+) accelerate inclusion formation in DA neurons, while astrocyte co-culture (GFAP+) confers neuroprotection — establishing the cellular circuitry of neurodegeneration and enabling therapeutic screening against individual glial components.

Fig. Microglia–DA neuron co-culture (IBA1 / TH)

Fig. Astrocyte–DA neuron co-culture (GFAP / TH)

Fig. IFN-γ–induced autophagy dysregulation — LC3B accumulation

Anti-Cytokine Biologics Rescue

Anti-TNFα, anti-IL-1β, and anti-IL-6 biologics — alone and in combination — rescue TH+ neuron survival under dual-hit conditions, supporting a translational hypothesis for immunomodulatory neuroprotection in Parkinson's disease.

Electron Microscopy of Lewy-Like Pathology

Transmission electron microscopy (TEM) and super-resolution STED nanoscopy resolve the ultrastructure of α-synuclein inclusions at fibrillar and sub-lysosomal resolution. Collected images document Lewy-body-like inclusions in cell bodies, Lewy-neurite-like aggregates in processes, compact/mature inclusions matching patient tissue morphology, and nanogold-labeled fibrils inside intact and ruptured lysosomes.

Fig. EM montage — Lewy-body-like inclusions across iPSC-DA neurons

Fig. Compact/mature inclusion matching patient tissue morphology

Fig. TEM 98 000× — nanogold-labeled α-synuclein fibrils in a lysosome

Fig. Thioflavin-S — amyloid core of mature α-synuclein inclusions

Parkin Agonism & Lysosomal-Rescue Compounds

In collaboration with chemical biologists, I characterized a Parkin-activating hybrid (PAH) small-molecule series in iPSC dopaminergic neurons. PAHs dose-dependently reduced α-synuclein inclusion burden, restored TH+ neuron survival, and normalized pharmacodynamic markers (pSyn, TFEB, NRF2, LAMP1/2, HDAC6). A complementary Telomerase-Activating Compound (TAC) program targets mitochondrial–lysosomal resilience and also reduced α-synuclein pathology. This neuroprotection program directly generalizes to dystonia: lysosomal rescue and mitochondrial-quality-control agonism are mechanistically attractive for basal-ganglia neurons under proteostatic stress.

Fig. PAH dose-response — α-synuclein inclusion reduction in iPSC-DA neurons

Fig. PAH pharmacodynamic panel — α-syn, pSyn, TFEB, NRF2, LAMP1/2, HDAC6

Functional Genomics for Mitophagy & α-Synuclein Uptake

Two CRISPR-screening campaigns directly relevant to movement-disorder biology. (1) A genome-wide CRISPR knockout screen in iPSC-derived dopaminergic neurons identifying PARK2-dependent mitophagy regulators and neuroprotective targets (manuscript under review at Nature). (2) An arrayed CRISPR screen in RPE1 cells defining RAC1-dependent macropinocytosis as the principal route for α-synuclein preformed-fibril internalization (Cell Reports, 2022; 50+ citations).

Transcriptomics & Proteomics Integration

Label-free and TMT (6-/10-/16-plex) LC-MS/MS proteomics, scRNA-seq, and bulk RNA-seq with GSEA / GO / KEGG pathway analysis integrate across the dual-hit model to map dysregulated networks — a framework that transfers naturally to dystonia patient-line profiling.

Extending the Platform to Dystonia & Movement Disorders

Dystonia, like Parkinson's disease, is a disorder of motor control rooted in basal-ganglia and cortico-striatal circuitry. My platform is well suited to dystonia research even where direct dystonia data is not yet shown: the capabilities, models, and readouts below are the same ones that advance dystonia mechanism and therapeutics.

Translatable Capabilities

• iPSC differentiation into midbrain dopaminergic, cortical excitatory, and neural-progenitor populations (adaptable to medium-spiny-neuron / striatal-progenitor protocols)
• CRISPR editing of movement-disorder genes on patient-derived or isogenic backgrounds (TOR1A/DYT1, GNAL, THAP1, KMT2B, ANO3, SGCE, ATP1A3)
• MEA electrophysiology and calcium imaging to quantify firing-rate, burst, and synchrony phenotypes — directly relevant to the abnormal network activity underlying dystonia
• High-content confocal & STED imaging with automated morphometry (AutoMorphoTrack) for neurite, synaptic, and aggregate phenotypes
• Proteomics & scRNA-seq for unbiased molecular phenotyping of patient lines
• Neuroinflammation assays increasingly implicated in dystonia pathophysiology
• Small-molecule & biologic screening with multi-modal pharmacodynamic readouts

Shared Biology, Shared Tools

Parkinson's disease and dystonia share basal-ganglia circuit dysfunction, alterations in dopaminergic signaling, and — in a growing number of genetic forms — proteostasis and organelle-quality-control deficits (e.g., TOR1A / torsinA at the nuclear envelope and ER, lysosomal biology in KMT2B-associated dystonia). The same iPSC-derived neuron models, CRISPR-edited lines, imaging, and pharmacodynamic panels that power my Parkinson's work are a ready-to-deploy foundation for mechanistic and translational dystonia studies.

Fig. iPSC differentiation platform — adaptable across dopaminergic, cortical, and striatal-adjacent lineages

Selected Parkinson's-Relevant Publications

• Gong Y, Bayati A, et al. — Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small-molecule Parkin agonism — Nature, under review (2026) · first co-author
• Recinto SJ, MacDonald A, Premachandran S, Liu L, Bayati A, et al. — Myeloid PINK1 represses mtDNA release and immune signaling that impacts neuronal pathology in patient-derived idiopathic PD models (2026)
• Schumacher JG, Zhang X, Macklin EA, Wang J, Bayati A, et al. — Baseline α-synuclein seeding activity and disease progression in sporadic and genetic PD — PPMI cohort (2025)
• Bayati A, Schumacher JG, Chen — AutoMorphoTrack: a modular framework for organelle morphology, motility & colocalization — bioRxiv 2025.07.19.665650 (2025)
• Bayati A, Ayoubi R, Aguila A, Zorca CE, Deyab G, Han C, Recinto SJ, et al. — Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines — Nature Neuroscience 27:2401–2416 (2024) · first & corresponding author
• Bayati A, McPherson PS — Alpha-synuclein, the autophagy-lysosomal pathway, and Lewy bodies: mutations, propagation, aggregation, and formation of inclusions (invited review, 2024)
• Bayati A, Luo W, Del Cid-Pellitero E, Fon EA, Durcan TM, McPherson PS — Visualization of α-synuclein trafficking via nanogold labeling and electron microscopy — STAR Protocols 4:102113 (2023)
• Bayati A, Banks E, Han C, Luo W, Wolfgang WR, Zorca CE, et al. — Rapid macropinocytic transfer of α-synuclein to lysosomes — Cell Reports 40:111102 (2022) · first author
• Bayati A, Kumar R, Francis V, McPherson PS — SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis — Journal of Biological Chemistry 296:100306 (2021) · 570+ citations

Further detail and additional publications are available on the Publications page, and related cross-cutting work on drug discovery, iPSC models, neuroimmunology, genetics, microscopy, and biomarkers.