Syndecans uptake of aggregate proteins in neurodegenerative diseases
=> AD: GSK3, APOE, DPYSL2, MAP1B, PTP1B, RTN1. STMN1.
PD: hnRNPK, PARK7.
NeuroMMSig syndecan subgraph:
Fundamental mechanisms underlying the biological processes governing the cellular spreading of pathologically misfolded proteins in AD and PD. Letoha et al. (PHI) pursued these objectives with established cellular platforms overexpressing distinct isoforms of syndecans (SDCs), a heparan sulfate proteoglycan (HSPG) family with established role in mediating intracellular delivery of various macromolecular entities including growth factors, viruses and bacteria.
Cartoon of the candidate mechanism:
To study the SDC-mediated endocytosis of misfolded proteins, PHI developed several assays overexpressing SDC families and their deletion mutants, providing valuable methods for studying the cellular internalization and intracellular route of protein aggregates (β-amyloid [Aβ], tau and α-synuclein). PHI assessed several aspects of SDC dependent cellular uptake of misfolded protein aggregates, including: i) membrane attachment and interaction with SDCs, ii) internalization and related signaling pathways and iii) intracellular transport iv) effects of ApoE isoforms on these interactions. They found that SDCs, especially SDC3, the neuron specific isoform of the SDC, attach and deliver Aβ, tau and α-synuclein into the cytosol.