Light chain amyloidosis (AL) is a devastating disease caused by the clonal expansion of a malignant plasma cell that secretes a destabilized, amyloidogenic immunoglobulin light chain (LC). Amyloidogenic LCs undergo misfolding and concentration-dependent aggregation into toxic oligomers and amyloid fibrils that deposit on distal tissues such as the heart. Thus, AL patients suffer from both a plasma cell malignancy and a systemic amyloid disease. Current AL treatments use chemotherapy and autologous stem cell replacement to decrease the clonal plasma cell population, only indirectly affecting AL amyloid pathology. While this approach is efficient for 70% of patients, the remaining 30% of patients are too sick from LC proteotoxicity to tolerate this treatment. In order to treat these patients, new therapies must be developed to treat the LC proteotoxicity in AL pathology. A challenge in developing such strategies is the heterogeneity of AL-associated, amyloidogenic LC sequences. Thus, any strategy to ameliorate AL amyloid pathology must target a fundamental biologic mechanism that mediates toxicity of heterogeneous amyloidogenic LCs, but does not globally compromise organismal immunity or secretion of the endogenous secreted proteome. We hypothesize that the activity of endoplasmic reticulum (ER) proteostasis pathways is a critical determinant in toxic LC aggregation that can be targeted to ameliorate AL amyloid pathology. ER proteostasis pathways can facilitate secretion of destabilized, amyloidogenic proteins, increasing their serum concentrations available for toxic misfolding and aggregation. Thus, modulating the activity of ER proteostasis pathways offers a unique opportunity to reduce serum concentrations of destabilized, amyloidogenic LCs and thus decrease proteotoxic LC aggregation. We show that adapting ER proteostasis pathways through stress-independent activation of select Unfolded Protein Response (UPR)-associated transcription factors reduces the secretion and extracellular aggregation of a destabilized, amyloidogenic LC, without affecting secretion of a non-amyloidogenic LC, IgGs or the global endogenous secreted proteome. Here, we define the contribution of ER proteostasis pathways in toxic LC aggregation by identifying pathways preferentially involved in the secretion, extracellular aggregation and subsequent toxicity of amyloidogenic LCs. Furthermore, we will demonstrate that small molecule ER proteostasis regulators that alter the activity of these ER proteostasis pathways reduce secretion and toxic aggregation of destabilized, amyloidogenic LCs in AL patient-derived plasma cells. Through these efforts, we will show that the activity of ER proteostasis pathways is a fundamental determinant in dictating AL amyloid pathology. Furthermore, we will identify first-in-class small molecule ER proteostasis regulators that target these pathways to attenuate secretion and toxic aggregation of amyloidogenic LCs. Our results will establish ER proteostasis regulation as the first strategy to ameliorate AL amyloid pathology that can then be used in combination with chemotherapeutics to treat the AL patient cohort suffering from severe LC proteotoxicity.
Light Chain Amyloidosis is a devastating disease characterized by the clonal expansion of a cancerous plasma cell population that secretes a destabilized, amyloidogenic immunoglobulin light chain. Current therapies to treat this disease use chemotherapeutics to ablate the cancerous plasma cell population, but this approach is insufficient for a large population of patients suffering from severe proteotoxicity caused by the misfolding, aggregation and deposition of the secreted amyloidogenic light chain on tissues such as the heart. Here, we establish a first-in-class small molecule strategy to ameliorate amyloidogenic light chain proteotoxicity by reducing the secretion of amyloidogenic light chains from the cancerous plasma cell, providing a new therapeutic paradigm that can be employed in combination with chemotherapeutics to treat the Light Chain Amyloidosis patients suffering from severe proteotoxic damage on distal tissues.
| Cole, Kyle S; Grandjean, Julia M D; Chen, Kenny et al. (2018) Characterization of an A-Site Selective Protein Disulfide Isomerase A1 Inhibitor. Biochemistry 57:2035-2043 |
| Paxman, Ryan; Plate, Lars; Blackwood, Erik A et al. (2018) Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. Elife 7: |
| Chen, Kai-Chun; Qu, Song; Chowdhury, Saikat et al. (2017) The endoplasmic reticulum HSP40 co-chaperone ERdj3/DNAJB11 assembles and functions as a tetramer. EMBO J 36:2296-2309 |
| Plate, Lars; Wiseman, R Luke (2017) Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy. Trends Cell Biol 27:722-737 |
| Plate, Lars; Cooley, Christina B; Chen, John J et al. (2016) Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. Elife 5: |
