A new study led by Van Andel Institute and KU Leuven scientists has linked bladder inflammation from urinary tract infections (UTIs) with an increased risk of developing multiple system atrophy (MSA), a rare neurodegenerative disease with few treatments and no cure.

The findings, published in the journal Acta Neuropathologica, offer an extraordinary glimpse into MSA’s earliest stages and give scientists a potentially powerful — and desperately needed — target for developing new therapies.

Like many neurodegenerative diseases, MSA is likely caused by clumps of abnormal proteins that clog and eventually kill cells in the brain and nervous system. As these vital cells are lost, people experience progressively worsening symptoms: movement difficulties, breathing challenges, irregular blood pressure and more. The protein involved in MSA is called alpha-synuclein.

Proteins are the workhorses of the body and play critical roles in virtually every process that keeps us healthy. Their ability to do their jobs is tied to their shape, much like the way a key fits only into its designated lock. Occasionally, something happens that causes proteins to become misshapen, which prompts them to form clumps called aggregates.

It’s this “something” that the research team sought to solve — what event pushes normal proteins to transform into harmful ones?

In MSA, one answer appears to be inflammation. The study revealed that bladder inflammation caused by UTIs can trigger alpha-synuclein proteins to form aggregates, which then migrate through the nerves to the brain. Once there, they continue to spread and, in some cases, cause MSA.

About 1 in 25,000 people is affected by MSA. UTIs increased the risk of developing the disease three-fold, the study revealed.

UTIs are common and most people who experience them do not go on to develop MSA. However, by identifying bladder inflammation as a risk factor, the research team has shed new light on MSA’s largely mysterious origins and paved the way for new research into treatments that may slow or stop disease progression.

The findings mirror results from a growing number of Parkinson’s disease studies that pinpoint inflammation as a trigger for protein aggregation. Many studies also suggest this process may begin in the gut rather than the brain. Parkinson’s and MSA share many similarities — both are linked to alpha-synuclein, both impact the brain and nervous system, and both can be challenging to definitively diagnose. In many cases, MSA is initially misdiagnosed as Parkinson’s.

The study’s corresponding author is Patrik Brundin, M.D., Ph.D., who served as VAI’s Deputy Chief Scientific Officer before moving to Roche in 2022. Its first author is Wouter Peelaerts, Ph.D., an assistant professor at KU Leuven who completed a postdoctoral fellowship in Brundin’s lab at VAI. VAI’s Lena Brundin, M.D., Ph.D., Michael Henderson, Ph.D., and J. Andrew Pospisilik, Ph.D., also are study co-authors.

Other authors include: Gabriela Mercado, Ph.D., Sonia George, Ph.D., Alysa Kasen, Miguel Aguileta, Ph.D., Christian von Linstow, Ph.D., Emily Kuhn, Lucas Stetzik, Ph.D., Rachael Sheridan, Ph.D., Liza Bergkvist, Ph.D., Lindsay Meyerdirk, Allison Lindqvist, Martha L. Escobar Galvis, Ph.D., and Jennifer A. Steiner, Ph.D., of VAI; Marie Villumsen, Ph.D., Tomasz Brudek, Ph.D., and Susana Aznar, Ph.D., of Bispebjerg and Frederiksberg Hospital; Alexandra B. Sutter of University of Michigan; Chris van den Haute, Ph.D., and Veerle Baekelandt, Ph.D., of KU Leuven; Scott J. Hultgren, Ph.D., and Tom J. Hannan, DVM, Ph.D., of Washington University School of Medicine; and Magdalena I. Ivanova, Ph.D., of Northwestern University Feinberg School of Medicine.

Research reported in this publication was supported by Van Andel Institute; a Fulbright Postdoctoral Fellowship (Peelaerts); an Integrated DNA Postdoctoral Fellowship (Peelaerts); a FWO Flanders Postdoctoral Fellowship (Peelaerts); the Farmer Family Foundation (P. Brundin); and the American Parkinson’s Disease Association (Ivanova). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.

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