Characterization of plasma membrane-associated lipid rafts in neurodegenerative disease models and their impact on protein aggregation dynamics

Project Abstract

Lipid rafts within plasma membranes are dynamic, cholesterol-rich microdomains that organize signaling networks and trafficking pathways, and their perturbation has been implicated in the pathogenesis of neurodegenerative diseases. This study investigates the characterization of plasma membrane-associated lipid rafts in cellular and animal models of neurodegeneration and elucidates how raft composition and organization influence the nucleation and progression of protein aggregation, with a focus on amyloidogenic and tauopathies. We combine super-resolution imaging, biochemical partitioning, and mass spectrometry–based lipidomics to map raft microdomain architecture under disease-relevant conditions, including oxidative stress, mitochondrial dysfunction, and cholesterol dysregulation. We further quantify the coupling between raft integrity and the misfolding kinetics of aggregation-prone proteins such as beta-amyloid, alpha-synuclein, and hyperphosphorylated tau using real-time fluorescence assays and seeded aggregation models. By integrating crosslinking-immunoprecipitation and proximity labeling approaches, we delineate raft-associated interactomes that modulate chaperone activity, proteostasis, and endocytic trafficking, thereby altering clearance versus accumulation of misfolded species. The study also examines how lipid saturation, sphingolipid content, and cholesterol turnover influence membrane curvature and the nanoscale clustering of proteostasis regulators, providing mechanistic insight into how raft remodeling can shift the balance toward cytotoxic oligomers and intracellular inclusions. In disease-relevant neurons and glial cells, we manipulate raft dynamics pharmacologically and genetically to assess causal relationships with protein aggregation burden, intracellular localization patterns, and downstream neurotoxic signaling cascades such as ER stress, unfolded protein response, and inflammatory responses. Our results reveal that specific raft subdomains regulate the nucleation phase of aggregation by modulating the local concentration of aggregation-prone species and by organizing nucleation catalysts, whereas disruption of raft integrity accelerates clearance pathways or, conversely, promotes endolysosomal stagnation depending on the cellular context. We identify potential lipid and protein biomarkers within raft fractions that correlate with disease stage and aggregate load, offering translational biomarkers for assessing therapeutic interventions. The study also evaluates whether targeting raft components or altering lipid metabolism can attenuate aggregation progression and neuronal vulnerability in vivo, thus providing a rationale for raft-centered strategies in neurodegenerative disease modulation. Overall, the findings advance the understanding of how plasma membrane microdomain composition governs protein misfolding dynamics and identify novel targets for intervention aimed at stabilizing membrane organization and enhancing proteostasis to mitigate neurodegenerative outcomes.

Project Overview

What This Project Is About

---

A straightforward, non-technical overview of how cell membranes organize proteins and why this organization might matter in diseases like Alzheimer's or Parkinson's. It looks at tiny membrane regions called lipid rafts and how they affect the clumping of disease-related proteins.

---

---

The Problem It Addresses

---

Scientists still don’t fully understand how membrane organization influences protein aggregation, a hallmark of many neurodegenerative diseases. Without this knowledge, developing strategies to slow or prevent disease progression is harder.

---

---

Objectives of the Project

---

1. Describe what lipid rafts are and why they matter for protein behavior in brain cells.
2. Identify how changes in raft composition relate to protein clumping.
3. Assess methods to measure raft structure and protein aggregation in simple models.
4. Link membrane organization to functional readouts relevant to neurodegeneration.

---

---

What You Will Do Step by Step

---

1) Review basic literature on lipid rafts and protein aggregation. 2) Learn and apply safe lab-style techniques to observe membrane features in simple cell models. 3) Collect data on how raft changes correlate with protein clumping using accessible imaging or biochemical tests. 4) Analyze patterns to see if raft state predicts aggregation tendency. 5) Summarize findings in clear, non-technical terms.

---

---

---

---

Expected Outcome

The project should yield a clear explanation of whether and how membrane raft organization relates to protein aggregation, plus a set of approachable methods that could be used in introductory labs. The result will help students understand a key link in neurodegenerative disease research and highlight potential targets for further study.