Proteomics

Dataset Information

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MTOR inhibition ameliorates tau burden and neurofilament pathology in sporadic PSP-RS neurons

ABSTRACT: Progressive supranuclear palsy, Richardson’s syndrome subtype (PSP-RS), is a tauopathy marked by early axonal pathology and neurodegeneration. Modeling sporadic PSP-RS in human neurons remained a major challenge. Here, we generated midbrain dopaminergic (mDA) neurons from induced pluripotent stem cells (iPSCs) derived from idiopathic PSP-RS patients and healthy controls. Combined transcriptomic and proteomic analysis revealed reduced dopaminergic differentiation and synaptic function, alongside increased phosphorylated and oligomeric Tau, neurofilament accumulation, axonal swelling, and endoplasmic reticulum disorganization. These alterations coincided with impaired autophagic flux and elevated levels of phosphorylated mTOR. Pharmacological inhibition of mTOR restored autophagy and reduced neurofilament and tau pathology. Collectively, our findings implicate mTOR-dependent autophagy dysfunction as a key driver of early axonal pathology of PSP-RS and highlight autophagy modulation as a promising therapeutic avenue.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Dopaminergic Neuron, Cell Culture

DISEASE(S): Progressive Supranuclear Palsy

SUBMITTER: Caterina Gabriele  

LAB HEAD: Marco Gaspari

PROVIDER: PXD072104 | Pride | 2026-06-08

REPOSITORIES: Pride

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Dataset's files

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Action DRS
IdentifiedAndQuantifiedProteins.tsv Tabular
Neurons_PSP_1.raw Raw
Neurons_PSP_2.raw Raw
Neurons_PSP_3.raw Raw
Neurons_PSP_4.raw Raw
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Publications

Cytoskeletal Imbalance and Axonal Vulnerability in Sporadic PSP-RS: Early Changes in a Human iPSC-Derived Neuronal Model with Altered mTOR Signaling.

Covello Raffaele R   Benedetto Giorgia Lucia GL   Scalise Stefania S   Gabriele Caterina C   Valente Desirèe D   Zannino Clara C   Puccio Barbara B   Quattrone Andrea A   Guzzi Pietro Hiram PH   Gaspari Marco M   Quattrone Aldo A   Cuda Giovanni G   Parrotta Elvira Immacolata EI  

Cells 20260423 9

Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is a primary 4R tauopathy in which early axonal dysfunction may precede overt neurodegeneration; however, the mechanisms linking Tau dysregulation to cytoskeletal vulnerability remain poorly defined. Here, we generated induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons from individuals with sporadic PSP-RS and matched healthy controls and performed integrated transcriptomic and proteomic analyses. PSP-RS neuron  ...[more]

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