Type 2 diabetes as a protein misfolding disease

Mukherjee, Abhisek; Morales-Scheihing, Diego; Butler, Peter C.; Soto, Claudio

doi:10.1016/j.molmed.2015.04.005

Cited by 280 publications

(222 citation statements)

References 158 publications

(174 reference statements)

Supporting

Mentioning

217

Contrasting

Unclassified

Order By: Relevance

“…Cellular aggregates are associated with many diseases, including neurodegeneration (Aguzzi and Lakkaraju, 2016), type II diabetes (Mukherjee et al, 2015), systemic amyloidosis (Blancas-Mejia and Ramirez-Alvarado, 2013), and even aging (Lopez-Otin et al, 2013). However, it is also becoming clear that protein aggregates have beneficial functions in many biological processes.…”

Section: Introductionmentioning

confidence: 99%

A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance

Newby

Kiriakov

Hallacli

et al. 2017

Cell

View full text Add to dashboard Cite

SUMMARY Protein aggregation is a hallmark of many diseases, but also underlies a wide range of positive cellular functions. These phenomena have been difficult to study due to a lack of quantitative and high-throughput cellular tools. Here we develop a synthetic genetic tool to sense and control protein aggregation. We apply the technology to yeast prions, developing sensors to track their aggregation states and employing prion fusions to encode synthetic memories in yeast cells. Utilizing high-throughput screens, we identify prion-curing mutants and engineer “anti-prion drives” that reverse the non-Mendelian inheritance pattern of prions and eliminate them from yeast populations. We extend our technology to yeast RNA-binding proteins (RBPs) by tracking their propensity to aggregate, searching for co-occurring aggregates, and uncovering a group of coalescing RBPs through screens enabled by our platform. Our work establishes a quantitative, high-throughput, and generalizable technology to study and control diverse protein aggregation processes in cells.

show abstract

Section: Introductionmentioning

confidence: 99%

A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance

Newby

Kiriakov

Hallacli

et al. 2017

Cell

View full text Add to dashboard Cite

show abstract

“…1,2 It is at present one of the three major conditions that endanger human health (the others being cancer and cardiovascular disease). 3 Over the past 20 years, the incidence of diabetes has increased sharply.…”

Section: Introductionmentioning

confidence: 99%

Glucose- and temperature-sensitive nanoparticles for insulin delivery

Wu¹,

Williams²,

Li³

et al. 2017

IJN

View full text Add to dashboard Cite

Glucose- and temperature-sensitive polymers of a phenylboronic acid derivative and diethylene glycol dimethacrylate (poly(3-acrylamidophenyl boronic acid- b -diethylene glycol methyl ether methacrylate); p(AAPBA- b -DEGMA)) were prepared by reversible addition–fragmentation chain transfer polymerization. Successful polymerization was evidenced by 1 H nuclear magnetic resonance and infrared spectroscopy, and the polymers were further explored in terms of their glass transition temperatures and by gel permeation chromatography (GPC). The materials were found to be temperature sensitive, with lower critical solution temperatures in the region of 12°C–47°C depending on the monomer ratio used for reaction. The polymers could be self-assembled into nanoparticles (NPs), and the zeta potential and size of these particles were determined as a function of temperature and glucose concentration. Subsequently, the optimum NP formulation was loaded with insulin, and the drug release was studied. We found that insulin was easily encapsulated into the p(AAPBA- b -DEGMA) NPs, with a loading capacity of ~15% and encapsulation efficiency of ~70%. Insulin release could be regulated by changes in temperature and glucose concentration. Furthermore, the NPs were non-toxic both in vitro and in vivo. Finally, the efficacy of the formulations at managing blood glucose levels in a murine hyperglycemic diabetes model was studied. The insulin-loaded NPs could reduce blood glucose levels over an extended period of 48 h. Since they are both temperature and glucose sensitive and offer a sustained-release profile, these systems may comprise potent new formulations for insulin delivery.

show abstract

“…However, not many studies have been done in this regard. From our extensive experience studying PMDs of the CNS and considering the current evidence that implicates IAPP aggregates in T2D pathology (Mukherjee et al 2015), we argue that IAPP aggregates ( perhaps smaller, soluble oligomers) may play a key role in contributing to T2D. The possibility that IAPP aggregates might propagate from islet to islet or even from individual to individual certainly presents a new area of research.…”

Section: Future Directionsmentioning

confidence: 97%

“…However, overexpression of the human IAPP sequence in rodents resulted in the accumulation of IAPP aggregates in islets, leading to clinical and pathological hallmarks of T2D (Janson et al 1996;Matveyenko and Butler 2006). In a recent review, we summarized the mechanism of IAPP aggregate formation and toxicity and established a detailed comparison with other protein aggregates associated with PMDs of the central nervous system (CNS), such as amyloid-b (Ab) and tau in AD, a-synuclein in PD, or prions in prion diseases (Mukherjee et al 2015). Here, we will focus on the possibility of prion-like propagation of IAPP aggregates and their putative role in T2D.…”

Section: Type 2 Diabetes and Iapp Aggregatesmentioning

confidence: 99%

Prion-Like Protein Aggregates and Type 2 Diabetes

Mukherjee

Soto

2017

Cold Spring Harb Perspect Med

Self Cite

View full text Add to dashboard Cite

Type 2 diabetes (T2D) is a highly prevalent metabolic disease characterized by chronic insulin resistance and b-cell dysfunction and loss, leading to impaired insulin release and hyperglycemia. Although the mechanism responsible for b-cell dysfunction and death is not completely understood, recent findings suggest that the accumulation of misfolded aggregates of the islet amyloid polypeptide (IAPP) in the islets of Langerhans may play an important role in pancreatic damage. Misfolding and aggregation of diverse proteins and their accumulation as amyloid in different organs is the hallmark feature in a group of chronic, degenerative diseases termed protein misfolding disorders (PMDs). PMDs include highly prevalent human illnesses such as Alzheimer's and Parkinson's disease, as well as more than 25 rarer disorders. Among them, prion diseases are unique because the pathology can be transmitted by a proteinaceous infectious agent, termed a prion, which induces disease by propagating protein misfolding and aggregation. This phenomenon has a striking resemblance to the process of protein misfolding and aggregation in all of the PMDs, suggesting that misfolded aggregates have an intrinsic potential to be transmissible. Indeed, recent studies have shown that the pathological hallmarks of various PMDs can be induced in vivo under experimental conditions by inoculating tissue extracts containing protein aggregates into animal models. In this review, we describe our current understanding of the molecular mechanism underlying the prion-like transmission of protein aggregates and its possible role in T2D.

show abstract

Type 2 diabetes as a protein misfolding disease

Cited by 280 publications

References 158 publications

A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance

A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance

Glucose- and temperature-sensitive nanoparticles for insulin delivery

Prion-Like Protein Aggregates and Type 2 Diabetes

Contact Info

Product

Resources

About