The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Abstract

Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.

Sequestration of TDP-43216-414aggregates by cytoplasmic expression of the proSAAS chaperone

“…Figure 7A, bottom row depicts a representative Neuro2A cell. The fact that expression of excess cyto-proSAAS can efficiently block the cytosolic aggregation of Cherry-cyto-proSAAS supports the general anti-aggregant functions of proSAAS previously documented for Abeta 1-42, α-synuclein, and islet amyloid polypeptide (Hoshino et al, 2014;Jarvela et al, 2016;Peinado et al, 2013).…”

“…Prior work has shown that proSAAS, a small unglycosylated protein chaperone which contains no α-crystallin domain, is able to block and/or prevent the aggregation of proteins directly involved in neurodegenerative disorders, including Abeta and α-Syn (Hoshino et al, 2014;Jarvela et al, 2016). ProSAAS, found specifically in tissues such as neurons and endocrine cells which contain a regulated secretory pathway, has been found to be associated with plaques, Lewy bodies, and other brain aggregates in AD, PD and FTLD (Jarvela et al, 2016;Kikuchi et al, 2003). However, whether proSAAS directly affects the formation of intracellular aggregates has not been examined in living cells.…”

“…The contribution of coiled-coil domains to phase separation in the formation of membrane-less organelles such as P granules and promyelocytic leukemia nuclear bodies has been previously documented (reviewed in (Mitrea and Kriwacki, 2016)). ProSAAS also contains a predicted intrinsically disordered domain rich in prolines and alanines (residues 120-170); indeed, this region represents the most conserved portion of this protein (Jarvela et al, 2016;Kudo et al, 2009). The importance of disordered regions, including the contribution of prion-like domains, in phase transitions that lead to the formation of biomolecular condensates has been extensively reviewed (Banani et al, 2017;Gomes and Shorter, 2019).…”

“…We have previously reported that a neuronal secretory chaperone, proSAAS, potently blocks the aggregation of neurodegenerative disease-related proteins. Using in vitro assays, we showed that recombinant proSAAS blocks the assembly of both β-amyloid and α-Syn aggregation into fibrils, and is cytoprotective against oligomers of these two proteins (Hoshino et al, 2014;Jarvela et al, 2016). The likelihood of an important role for proSAAS in processes related to neurodegenerative disease is supported by the observation that proSAAS immunoreactivity colocalizes with inclusion bodies in a variety of neurodegenerative diseases (Hoshino et al, 2014;Jarvela et al, 2016;Kikuchi et al, 2003;Wada et al, 2004).…”

“…Using in vitro assays, we showed that recombinant proSAAS blocks the assembly of both β-amyloid and α-Syn aggregation into fibrils, and is cytoprotective against oligomers of these two proteins (Hoshino et al, 2014;Jarvela et al, 2016). The likelihood of an important role for proSAAS in processes related to neurodegenerative disease is supported by the observation that proSAAS immunoreactivity colocalizes with inclusion bodies in a variety of neurodegenerative diseases (Hoshino et al, 2014;Jarvela et al, 2016;Kikuchi et al, 2003;Wada et al, 2004). Lastly, thus far seven independent proteomics studies have identified proSAAS as a differentially expressed biomarker in cerebrospinal fluid obtained from Alzheimer's disease patients (Abdi et al, 2006;Choi et al, 2013;Finehout et al, 2007;Holtta et al, 2015;Jahn et al, 2011;Spellman et al, 2015;Wang et al, 2016), and transcriptomics studies of Alzheimer's brain tissue show that proSAAS expression increases during disease progression (Mathys et al, 2019).…”