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Smooth production in the brain factory: A breakthrough in Alzheimer’s research, Part One

Em Collins • 2/13/19

Smooth production in the brain factory: A breakthrough in Alzheimer’s research, Part One

Lahiri lab team: Trainees at different levels learning skills with grace and smile. Front row: L to R- Baindu Bayon (graduate student); Justin Long (MSTP student); Jason Bailey (graduate student); Back row: L to R- Nipun Chopra (graduate student); Debomoy Lahiri (Mentor and the PI); Andrew Fisher (summer trainee). Their current affiliations are listed at the end. Not in the photo: Bryan Maloney (Research analyst); Balmiki Ray, MD (postdoctoral medical fellow); John Spence, PhD (postdoctoral fellow)

Dozens of journals and books line the perimeter of his office; some opened; some bookmarked with the intention of finishing later; and all of them about Alzheimer’s and the research aiming to  provide early diagnosis and eventually treatment.

Behind his desk, Debomoy Lahiri, PhD leans back in his chair, arms crossed on his lap, his face content. In front of him sits the paper he senior-authored that was published in the high-impact factor journal, Molecular Psychiatry. When asked why his research is unique, his eyes light up and the corners of his mouth turn up to form a smile. With little hesitation, Lahiri begins to talk about his recent findings and how this research could potentially treat such a devastating disease.

What does your laboratory do?
It is essential to know the importance of microRNAs and the role they play. For the research community, microRNAs have a name–generally a number after “miRNA” (e.g., miR-20), like a factory order might have a number, and miRNAs each have a “seed sequence”, which identifies their targets. My laboratory studies the biology of these tiny molecules (miRNA) and how they affect human health and diseases.
Just in case there is any confusion, this is not the “stop codon” that is found on all mRNAs. The stop codon is the signal “this is the end of the protein.” It does not determine how much of that protein is made. That is what regulators like miRNA do. Also, miRNAs don’t work by themselves, they are part of a complex of proteins and RNA called “RISC.” Like every other biological discovery, it may start out looking simple, but it ultimately is connected to many other factors.

What did your research find?
Imagine a factory line. For assembly to be efficient, you need signals that control the flow and  number of pieces that go through the line. Any malfunction can cause shutdowns or create chaos. Disease is an analogy of a factory out of control, with some sections piling up parts that can go nowhere and others  with no parts to process. Production works the best when everything synchronizes perfectly.

Lahiri lab team: Trainees applying skills with great focus and attention using modern tools. Front -Justin Long; Back- Nipun Chopra. Both are discovering how small microRNA species could exert large effects at cellular level in the body- either maintaining normal function or causing dysfunction as in Alzheimer’s disease

Unusual species of microRNA may be the missing link for treatments. As they regulate gene products implicated in Alzheimer’s, microRNA expression will also alter levels of amyloid-beta. Therefore, they may serve as a novel drug targets in Alzheimer’s disease.
Discovering microRNAs that can turn down production of important Alzheimer’s disease elements is crucial to research. My team found something that could be even bigger: all of these gene regulators naturally produced by the human body can serve as a targets in Alzheimer’s disease.

My lab team members, including medical, graduate students and postdocs have looked at several microRNAs over the years. Three of these are miR-101, miR-153, and miR-339, published in another elite journal, Jounral of Biological Chemistry. We found that they play critical roles in Alzheimer’s disease. For miR-101, it regulates beta-amyloid precursor protein (APP). For miR-153, it regulates APP and alpha synuclein (SNCA), and for miR-339, it regulates beta-amyloid site cleaving enzyme 1 (BACE1). These are all important in Alzheimer’s disease, because BACE1 cleaves APP to produce toxic amyloid-beta peptide (Abeta). Abeta-loaded plaque is a major component of  Alzheimer’s disease, possibly the most important component. Furthermore, SNCA may play a role in  Alzheimer’s and Parkinson’s disease.

What is microRNA and how does it differ from mRNA?
Messenger RNA, which transmits information for building proteins from the chromosome to the protein, acts as an instruction manual. There are several other types of RNA molecules that do not do this. These non-coding RNA molecules usually work to turn protein production up or down—they are regulators. MiRNAs  generally do two things. First, they slow down transcription of specific mRNAs to protein. Second, they target a part of an mRNA called the 3’-untranslated region (UTR).

How do the nuts and bolts of a miRNA machinery work? Typical miRNA activity. Messenger RNA (mRNA) is similar to a design template on a factory floor. The template (mRNA) is used by a casting or cutting machine or a press (ribosome) to produce a part (protein) according to the template instructions (mRNA). An microRNA (miRNA) is part of the control process. It identifies which specific mRNA is to be controlled. Control is actually provided by the complete complex of miRNA and the AGO protein (control system). The complete complex is also called “RISC”. RISC determines if and how much a template is used with a machine to produce less or more protein.

Can you provide some background on this discovery?
Alzheimer’s disease occurs when there is a buildup of amyloid-beta peptide (APP) in plaque in the brain. Why these plaques form remains a mystery, but finding ways to regulate and disrupt these plaques is where our research begins. The entire field of Alzheimer’s disease research has concluded that we have to start much earlier to treat it, possibly even before symptoms are found. Part of the normal function of APP is iron regulation; it removes excess iron from cells. Excess iron buildup is associated with Alzheimer’s, possibly before plaques even form. Shining any light on how APP is regulated in relationship to iron levels could provide a new avenue for dealing with this difficult disease. My team discovered activity by miR-346, which targets APP and upregulates APP translation and amyloid-beta production. Additionally, miR-346 overlaps with active sites of iron-responsive element, suggesting that a healthy amount of FeAR (Fe, APP, RNA) must exist to maintain APP homeostasis, or what is necessary for survival.

How long of a process has this been?
Several years. From actively contemplating the research and taking samples to treat with our method, to writing everything down for other researchers to learn from, this process took a long time. But it was worth it. It was excellent collaboration by bright graduate students, aspiring medical students, diligent research analysts and fellows. This experience has proven to me what I always tell my students: that hard work can pay off. You just need to be diligent.

Read part two of Lahiri’s interview.

 

Debomoy Lahiri, PhD, is a professor in neurobiology, psychiatry, and medical and molecular genetics Lahiri mentors MD, PhD students and postdoctoral fellows during their educational and training careers. Lahiri is the founding editor-in-chief for “Current Alzheimer Research”, a peer-reviewed international journal that reports the neurobiology, genetics, pathogenesis, and treatment approaches of Alzheimer’s disease, for over the last 15 years. He is the Research and Education Core (REC) leader of the federally funded Indiana Alzheimer Disease Center (IADC). Lahiri has authored/co-authored over 300 peer-reviewed articles and has received research funding uninterruptedly by NIH since 1992. Learn more about IU School of Medicine’s expertise in Alzheimer’s disease research and education.

Update: The trainees have moved on, with an important prefix, at different important places. Baindu Bayon, PhD, Health Scientist, NCATS, Division of Clinical Innovation, AAAS Policy Fellow, Washington DC; Jason Bailey, PhD, Senior Scientist, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN; Justin Long, MD, PhD, Knight ADRC Fellow, Department of Neurology, Washington University School of Medicine, St Louis, MO; Balmiki Ray, MD, Principal Neuroscientist (pharmacogenomics), Myriad Neuroscience, Mason, OH; John Spence, PhD, Research Associate, Department of Pediatrics, and Program Manager, Independent Investigator Incubator Program, Indiana Clinical and Transnational Sciences Institute and IU School of Medicine.

 

The views expressed in this post content represent the perspective and opinions of the author and may or may not represent the position of Indiana University School of Medicine.

Author

Em Collins

Communications Coordinator

Having joined IU School of Medicine in 2016, Em uses a poetry and theatre background to help bridge the academic world with the creative. A graduate of University of Evansville, he works with faculty and academic staff to formulate unique, marketing ideas that engage the public with innovative research at IU School of Medicine. From writing stories on groundbreaking equipment to orchestrating digital marketing strategies, Em collaborates with experts across the school to help departments thrive in their marketing and communication ambitions.Contact Em at emcolli@iu.edu.