In Vitro Interaction of a C-Terminal Fragment of TDP-43 Protein with Human Serum Albumin Modulates Its Aggregation.
Sadhana NirwalPreethi SaravananAkarsh BajpaiVini D MeshramGembali RajuWaghela DeekshaGanesan PrabusankarBasant K PatelPublished in: The journal of physical chemistry. B (2022)
An increased level of naturally occurring anti-TDP-43 antibodies was observed in the serum and cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis patients. Human serum albumin (HSA), the most abundant protein in blood plasma and CSF, is found to interact with pathological proteins like Aβ and α-synuclein. Therefore, we examined the effect on the in vitro aggregation of a C-terminal fragment of TDP-43 in the presence of HSA. We found that the lag phase in TDP-43 2C aggregation is abrogated in the presence of HSA, but there is an overall decreased aggregation as examined by thioflavin-T fluorescence spectroscopy and microscopy. An early onset of TDP-43 2C oligomer formation in the presence of HSA was observed using atomic force microscopy and transmission electron microscopy. Also, a known chemical inhibitor of TDP-43 2C aggregation, AIM4, abolishes the HSA-induced early formation of TDP-43 2C oligomers. Notably, the aggregates of TDP-43 2C formed in the presence of HSA are more stable against sarkosyl detergent. Using affinity copurification, we observed that HSA can bind to TDP-43 2C , and biolayer interferometry further supported their physical interaction and suggested the binding affinity to be in sub-micromolar range. Taken together, the data support that HSA can interact with TDP-43 2C in vitro and affect its aggregation.
Keyphrases
- amyotrophic lateral sclerosis
- early onset
- human serum albumin
- single molecule
- cerebrospinal fluid
- atomic force microscopy
- end stage renal disease
- high speed
- chronic kidney disease
- mental health
- late onset
- high throughput
- binding protein
- small molecule
- transcription factor
- single cell
- amino acid
- mass spectrometry
- peritoneal dialysis
- electron microscopy
- endothelial cells
- big data