Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, an...

Balanced protein synthesis and degradation are crucial for proper cellular function. Protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin complex 1 (mTORC1). Quality of newly synthesized polypeptides is maintained by the molecular chaperone and ubiquitin-proteasome systems. Little is known about how cells integrate information about the ...

Protein misfolding diseases are becoming increasingly prevalent with the increase in life expectancy and lifestyle changes over last century, constitute a health challenge at global level. Macroscopic protein deposits of amyloids associated such as Alzheimer’s (tau β-amyloid) Parkinson’s (α-synuclein). The mechanisms aggregation poorly understood, knowledge would enable rational design therapeu...

Prion diseases are fatal neurodegenerative that affect mammals, including humans. The hallmark of prion is the protein: misfolded and aggregated form protein PrPSc binds to cellular PrPC induces conformational conversion. Although gene polymorphisms correlate with varying degrees susceptibility host develop diseases, how residue substitutions modulate structural dynamics towards pathological mi...

The timescale for the microscopic dynamics of proteins during conformational transitions is set by the intrachain diffusion coefficient, D. Despite the central role of protein misfolding and aggregation in many diseases, it has proven challenging to measure D for these processes because of their heterogeneity. We used single-molecule force spectroscopy to overcome these challenges and determine...

Misfolding of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregat...

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