Extracellular Proteostasis and Chaperone Networks in Neurodegeneration

Dear Colleagues,

Proteostasis encompasses the cellular systems that regulate protein synthesis, folding, trafficking, and degradation to maintain protein homeostasis. Molecular chaperones, such as Hsp70, Hsp90, and small heat shock proteins (sHSPs), work in concert with co-chaperones, assist in protein folding, and prevent undesirable protein–protein interactions, and they are key players in intracellular proteostasis. However, some chaperones are constitutively secreted into the extracellular milieu and control undesirable protein–protein interactions and the clearance of extracellular misfolded proteins; the biology of these extracellular chaperones (ECs) is less well understood. Proteostasis is vital for neuronal health, and disruption is a central feature of aging and neurodegenerative diseases. A pathological hallmark of neurodegenerative disease is the accumulation of misfolded proteins. In motor neuron disease (MND), this includes Fused in Sarcoma (FUS), C9orf72 dinculeotide repeats, TAR DNA-binding protein 43 (TDP-43), and SOD1; in Alzheimer's disease, it includes extracellular Amyloid-β (Aβ) plaques and intracellular tau tangles; in Parkinson's disease, it includes alpha synuclein (α-syn)-rich Lewy bodies; and in Huntington's disease, it includes mutant huntingtin (Htt) protein aggregates. These proteinopathies reflect a breakdown in proteostasis, often exacerbated by impaired chaperone networks. This Special Issue explores the emerging roles of extracellular proteostasis and chaperone systems in neurodegeneration, highlighting novel insights into extracellular vesicle-mediated protein trafficking and therapeutic strategies utilizing extracellular chaperones aimed at restoring proteostatic balance.

Dr. Nicholas J. Geraghty
Guest Editor

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