Protein misfolding disorders (PMDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by the accumulation of misfolded protein aggregates in tissues including the brain. A few rare PMDs, such as bovine spongiform encephalopathy (BSE, or mad cow disease), and Creutzfeldt-Jacob Disease (CJD), can even be transmitted between humans or from animals to humans. In these cases, exposure to the causative misfolded protein aggregates, known as prions, triggers the transformation of normal proteins into the abnormal form. Effectively, prions “seed” the development of misfolded protein aggregation in the brain of the recipient, and this leads to the accumulation of toxic substances that destroy neurons. 

Protein aggregation isn’t limited to the widely recognized PMDs, however. About 90% of patients with type 2 diabetes (T2D) develop pancreatic islet deposits of the peptide hormone islet amyloid polypeptide (IAPP). These misfolded protein aggregates start accumulating many years before the clinical diagnosis of T2D, explain Abhisek Mukherjee, Ph.D., and Claudio Soto, Ph.D., who head a research team at McGovern Medical School at The University of Texas Health Science Center at Houston that studies the molecular basis of PMDs, including AD, PD, and prion diseases.

Previous post mortem and animal studies have suggested that islet IAPP aggregation is linked with key T2D features, including the loss of beta cell mass, but the how these IAPP deposits cause disease development or progression isn’t yet understood. One potential clue, however, is that “IAPP aggregates share similar structural features and mechanism of aggregation with prion aggregates,” Drs. Mukherjee and Soto told GEN.

The McGovern Medical School group has pioneered the hypothesis that diseases involving the accumulation of misfolded proteins might be transmissible using a similar mechanism to that by which infectious prions transmit disease. “Studies from our group and others have demonstrated that spreading and transmission of disease by propagation of protein misfolding is not exclusive of prion diseases, but that operates in the most prevalent protein misfolding diseases of brains, including AD and PD,” the two researchers commented.

The latest research by their group has now expanded that hypothesis to T2D, and for the first time demonstrated that the misfolded IAPP aggregates are indeed, like prions, transmissible and can trigger the development of T2D pathogenesis in the recipient. Using ex vivo and in vivo study methods and models similar to those used to investigate prion disease transmission, the team first demonstrated that synthetic IAPP aggregates could seed misfolding and aggregation of endogenous IAPP in islet cell cultures. They then showed that when experimental mice were inoculated with misfolded IAPP aggregates taken from human pancreatic tissue, the animals’ own IAPP started to transform into misfolded deposits in their pancreatic islets. IAPP aggregation was associated with the development of key pathologic features of T2D, including hyperglycemia, impaired glucose tolerance, and reduced beta cell number and mass.

The researchers aren't claiming that T2D is an infectious disease, like a cold or the flu, that people can easily “catch” from existing T2D patients. However, the studies, published today in The Journal of Experimental Medicine, have led the team to conclude that at least “some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.” Their published paper is titled “Induction of IAPP Amyloid Deposition and Associated Diabetic Abnormalities by a Prion-Like Mechanism.”

The new findings also have “profound implications for public health,” the researchers conclude, as transmission of IAPP aggregates to peripheral tissue would theoretically be less of a hurdle to infection than the transmission of prions across the blood–brain barrier into the brain. 

“One important conclusion of our studies from the point of understanding T2D is the potential role of IAPP misfolding and aggregation in the etiopathogenesis of the disease,” Drs. Mukherjee and Soto suggested to GEN. “Our results showing that induction of IAPP misfolding is sufficient to produce the main symptoms of the disease in the absence of any other process (such as high-fat diet or disruption of insulin signaling) suggest that IAPP misfolding and aggregation has an important role in the pathogenesis of T2D.”

“To our knowledge, this is the first work to show that IAPP aggregates from the diabetic pancreas can transmit disease pathology by a prion-like mechanism,” they added. “Our work not only extends the concept of prion-like transmission of protein aggregates to the most prevalent disease associated with protein aggregates, but also shows that transmission leads to bona fide disease phenotypes.… It is known that the islets containing IAPP aggregates show significant loss of β-cell area. Our work shows that the prion-like propagation of IAPP aggregates may have a key role in spreading the pathology from islet to islet during the progression of the disease.”

The research could also point to new therapeutic strategies. “The importance of our findings is not only limited to understanding the disease process and its origin, but may provide novel and immediate possibilities to prevent further spreading of the pathology as well as new targets for therapeutic intervention,” the researchers stressed to GEN. “For example, we believe, development of agents that can prevent IAPP aggregation or capture already formed IAPP aggregates will not only stop further damage of the islets but also may restrict the spreading of disease pathology from islet to islet. It is also possible to develop strategies to prevent the exposure to specific routes of transmission that may be particularly risky.”

Similarly, detecting IAPP aggregates in blood may provide a way of diagnosing T2D before symptoms develop. “In the brain PMDs, we have used the ability of the protein aggregates to spread the pathological characteristics as a way of detecting these structures in biological fluids. Indeed, the prion-like feature of IAPP aggregates may be utilized to develop a test that can detect people who might be on the way to develop the disease through a simple blood test.”

The McGovern Medical School team is now investigating the transmission properties of IAPP aggregates derived from human pancreas and blood. “We also plan to study in detail different routes of transmission, including oral administration and blood transfusion, two routes that have been shown to operate in prion diseases.” While work to date has been carried out ex vivo and in vivo in rodent models, if funding permits, the researchers would like to progress to studies in nonhuman primates.

“We think the next step will be to study the nature of the IAPP aggregates present in human pancreas, the potential sources of materials containing IAPP aggregates (e.g., blood, urine, etc.), and the putative routes by which IAPP aggregates may gain access to the body to transmit the disease,” Drs. Mukherjee and Soto added. “Furthermore, experimental transmission studies performed in large nonhuman primates will likely produce crucial information. These studies along with new epidemiological studies will help us understand to what extent T2D can be transmissible in humans.”

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