Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease

Abstract

Parkinson disease (PD) is characterized by dopaminergic neurodegeneration and intracellular inclusions of α-synuclein amyloid fibers, which are stable and difficult to dissolve. Whether inclusions are neuroprotective or pathological remains controversial, because prefibrillar oligomers may be more toxic than amyloid inclusions. Thus, whether therapies should target inclusions, preamyloid oligomers, or both is a critically important issue. In yeast, the protein-remodeling factor Hsp104 cooperates with Hsp70 and Hsp40 to dissolve and reactivate aggregated proteins. Metazoans, however, have no Hsp104 ortholog. Here we introduced Hsp104 into a rat PD model. Remarkably, Hsp104 reduced formation of phosphorylated α-synuclein inclusions and prevented nigrostriatal dopaminergic neurodegeneration induced by PD-linked α-synuclein (A30P). An in vitro assay employing pure proteins revealed that Hsp104 prevented fibrillization of α-synuclein and PD-linked variants (A30P, A53T, E46K). Hsp104 coupled ATP hydrolysis to the disassembly of preamyloid oligomers and amyloid fibers composed of α-synuclein. Furthermore, the mammalian Hsp70 and Hsp40 chaperones, Hsc70 and Hdj2, enhanced α-synuclein fiber disassembly by Hsp104. Hsp104 likely protects dopaminergic neurons by antagonizing toxic α-synuclein assemblies and might have therapeutic potential for PD and other neurodegenerative amyloidoses.

Reversing deleterious protein aggregation with re-engineered protein disaggregases

“…23,24 Hsp104 disassembles preformed α-syn amyloid fibers as well as its preamyloid oligomeric precursors. 23,24 In addition, Hsp104 suppressed α-syninduced dopaminergic neurodegeneration in the rat substantia nigra.…”

“…23,24 Hsp104 disassembles preformed α-syn amyloid fibers as well as its preamyloid oligomeric precursors. 23,24 In addition, Hsp104 suppressed α-syninduced dopaminergic neurodegeneration in the rat substantia nigra. 24 Furthermore, we have demonstrated that Hsp104 disassembles preformed aggregates and amyloids comprised of Aβ, tau, polyglutamine, and amylin in vitro.…”

“…20,22 While Hsp100 proteins are highly conserved in eubacteria and the vast majority of eukaryotes, Hsp104 from the budding yeast Saccharomyces cerevisiae is of particular interest, because it is the only protein known to rapidly disassemble amyloid and toxic preamyloid oligomers, but has no metazoan homolog. 20,[22][23][24] S. cerevisiae maintain a complex mechanism of genetic regulation requiring the construction and disassembly of yeast prions, and Hsp104 is critical in mediating these processes. 25 Our lab and others have explored applying Hsp104 to human disease models.…”

“…14, 23,24,26,27 In addition to applying native Hsp104, we have also aimed to engineer Hsp104 to have enhanced activity against different substrates implicated in neurodegeneration in an effort to restore proteostasis. 26 Recently, we reported the development of potentiated Hsp104 variants that disaggregate TDP-43, FUS, and α-syn.…”

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

“…For example, treating a polyglutamine disease model with an antiulcer drug, geranylgeranylacetone (GGA), which can induce the expression of different Hsps, could suppress the accumulation of pathogenic proteins and ameliorate the related phenotype (Katsuno et al 2005). In a rat model of Parkinson's disease, Hsp104 was found to be similarly efficient (Lo Bianco et al 2008). An increased level of expression of small Hsps and Hsp70 in the brain of AD patients has been reported in a number of studies (Perez et al 1991;Muchowski and Wacker 2005).…”