From left to right: Hugo Vicente Miranda, Paula Macedo and Luís Sousa
Hugo Vicente Miranda from the DysBrainD - Dysmetabolism in Brain Diseases - lab, along with PhD student Luís Sousa as first author, just published a systematic review on The Journal of Pathology, concerning Insulin-degrading enzyme (IDE). This enzyme is a crucial player in diabetes but its role in neurodegenerative diseases, such as Alzheimer's and Parkinson's, is not as well known. This work was performed in collaboration with the MEDIR: Metabolic Disorders lab from Paula Macedo, also with University of Aveiro and the Diabetes Portugal Education and Research Center (APDP-ERC).
You can read now what Hugo Miranda has to say about this research and how it may ellucidate the role of IDE in diseases other than diabetes.
What led you to prepare and publish this review?
There is a major gap in understanding why type-2 diabetes mellitus patients are at higher risk to develop neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. In this review we focused on insulin-degrading enzyme, and how its dysregulation plays a central pathogenic role in both diabetes and neurodegenerative diseases. We further propose insulin-degrading enzyme as a molecular player underlying the association between diabetes and these brain diseases.
Why is this important?
Since the majority of Parkinson’s and Alzheimer’s disease cases are of non-genetic origin, it is highly relevant to understand the impact of risk factors in the onset and development of these diseases. If we unveil the molecular links between diabetes and neurodegenerative diseases, not only we may identify novel drugs for therapeutics, but also discover molecular markers to identify the type-2 diabetes patients at higher risk to develop neurodegenerative diseases.
Can you use an analogy to help us understand this field?
Imagine you want to prepare a bowl of rice. You may use different types of rice, several recipes with different cooking times and styles. Sometimes, you unintentionally end up with sticky rice (aggregated rice). Both in Parkinson’s and Alzheimer’s disease, you have some types of proteins (rice) that are more prone to aggregate. However, we still do not know which mixed-up recipes drive these patients to develop sticky proteins in the brain that become neurotoxic. Provided we have a strong knowledge about the dysregulated processes underlying diabetes (bad recipes), we may evaluate if these may favor the formation of sticky proteins. If we find the cause, we can work on ways to prevent it, developing novel therapeutic avenues for these brain diseases.
What questions remain to be asked in this field that your group will pursue?
It is still unknown if insulin-degrading enzyme is dysregulated in Parkinson’s disease. Moreover, provided the chaperone-like function of this enzyme, it is also unclear if its increase may be able to suppress the pathogenicity of aggregation-prone proteins such as alpha-synuclein, whose pathology underlies the neurodegenerative events in Parkinson’s disease. At our lab, we are currently exploring these questions using both cellular and animal models of type-II diabetes mellitus and Parkinson’s disease. Moreover, in collaboration with both APDP and CNS-campus neurológico, we are further exploring the potential of insulin-degrading enzyme to diagnose Parkinson’s disease and/or to identify diabetes patients at higher risk of developing Parkinson’s disease.
The full article is titled Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases and can be found here. Also check out this video animation of the research done regarding IDE and its roles on neural cells:
Crosstalk between IDE and Alzheimer’s or Parkinson’s disease pathogenic pathways. (A) APP protein at neuronal plasma membrane and extracellular or membrane-bound IDE are internalised mainly via clathrin-mediated endocytosis. (B) APP amyloidogenic processing occurs at early endosomes by BACE1 and γ-secretases, forming Aβ peptides. IDE is reported at the lumen or membrane of early endosomes and may degrade Aβ or prevents its aggregation in these structures. (C) Throughout endosome maturation, the early endosomal membrane invaginates forming inner luminal vesicles giving rise to multivesicular bodies, which fuse with the plasma membrane and secrete cargo via exosomes or other exocytosis process, releasing amyloidogenic Aβ. IDE may process Aβ or prevent its aggregation in exosomes. (D) Extracellular Aβ may aggregate. However, extracellular IDE or membrane-bound IDE (facing the extracellular space) can degrade Aβ or prevent its aggregation. IDE impairment could result in higher accumulation of Aβ at early endosomes, exosomes, and extracellular space, increasing its pathologic aggregation. (E) Insulin binding to the insulin receptor triggers a signalling cascade that increase IDE levels and inhibit the activity of GSK3β. This active protein (F) increases the production of Aβ and (G) induces tau phosphorylation. Tau hyperphosphorylation induces its aggregation and leads to the formation of neurotoxic neurofibrillary tangles, a hallmark of AD. (H) Upon insulin binding, the insulin receptor is internalized via endocytosis. (I) In early endosomes, the insulin molecule may require removal for the receptor to be inactivated and (J) recycled back to the plasma membrane. Failure in IDE-mediated insulin receptor recycling may decrease insulin signalling (E), contributing to increased Aβ production. Insulin signalling failure also decreases IDE, which represents a vicious cycle with great impact in AD and PD pathogenesis. (K) Under pathological conditions, aSyn enters an amyloidogenic cascade, forming highly toxic oligomers and aggregates. IDE can suppress aSyn oligomerisation and toxicity. (L) aSyn species are reported in exosomes, where IDE may suppress aSyn aggregation and toxicity.