If you’ve ever heard of alpha-synuclein before, you may have heard it described in relation to Parkinson’s disease. Alpha-synuclein clumps in the brain; while doctors are still trying to determine the exact mechanism, many people believe these clumps to be disease-causing. But in reality, we all have alpha-synuclein in our bodies in the brain, heart, muscles, and other tissues. It’s only when this protein misfolds or becomes abnormal that it might become toxic.
According to an article by Marisa Wexler in Fabry Disease News, researchers and scientists have discovered that toxic alpha-synuclein clumps could also contribute to organ damage in Fabry disease.
What Kidney Biopsies Can Tell You
Initially, their study began by exploring the efficacy of enzyme replacement therapy (ERT). ERT delivers functional alpha-galactosidase A, an enzyme that breaks down fats like globotriaosylceramide. When these fats build up in cells, it can cause toxicity. The research team wanted to understand whether ERT could reverse cellular damage caused by this accumulation.
They began by taking kidney biopsies and examining a type of kidney cell called podocytes. After studying samples from patients with Fabry disease, some who were treated with ERT and others who were not, the researchers found high levels of globotriaosylceramide and signs of cellular damage. Even though ERT reduced globotriaosylceramide levels, the cellular damage remained.
Further examination used a podocyte cell line that replicated Fabry disease cells. In the findings, published in the Journal of Clinical Investigation, the researchers found that GLA-mutated cells had excess levels of alpha-synuclein. These levels were not reduced by ERT. It wasn’t until the research team utilized genetic engineering that alpha-synuclein levels fell. When these levels dropped, so did the hallmark signs of kidney damage.
Right now, there are therapies available that could be repurposed for alpha-synuclein reduction. The research team identified clenbuterol (in conjunction with ERT) and orciprenaline as beneficial for podocyte health. However, these options may not be safe for people with Fabry disease. More research is needed to determine how to address these heightened alpha-synuclein levels while also protecting a patient’s overall health.
Understanding Fabry Disease
Fabry disease is a rare genetic lysosomal storage disorder caused by GLA gene mutations. Globotriaosylceramide accumulation often begins in childhood and can cause several complications like strokes, heart attack, and kidney damage later in life. In the past, Fabry disease was thought to mostly affect males with females being carriers. However, more recent understandings of Fabry disease show that women can also show symptoms including pain, gastrointestinal distress, and renal involvement. Symptoms of Fabry disease may include hearing loss, tinnitus (ringing in the ears), corneal opacity, loss of ability to sweat (hypohidrosis), recurrent pain in the hands and feet, and small bundles of dark red spots on the skin, among others.
Right now, there are no cures for Fabry disease—but the FDA did just approve the first treatment for adults: Elfabrio. For younger individuals, their condition may be treated with ACE inhibitors, ERT, and a special diet that avoids certain fats.