JUPITER, Fla.—In March, The Scripps Research Institute (TSRI) announced two significant neurological discoveries, one dealing with the genetics of depression and one involving a link between neuronal death and Lewy bodies in Parkinson’s.
An estimated 10 million people worldwide are living with Parkinson’s disease, a neurodegenerative disorder that leads to an increasing loss of motor control. There are two hallmarks of the disease: a die-off of the brain cells that produce dopamine and protein clumps called Lewy bodies inside the neurons.
Dr. Corinne Lasmézas, a professor at the Florida campus of TSRI, believes a key to treating Parkinson’s disease is to study possible links between these two phenomena. Her research group has discovered a connection between neuronal death and Lewy bodies. The research, published recently in Proceedings of the National Academy of Sciences, proposes an explanation for why neurons die off in the first place.
“This study identifies the missing link between Lewy bodies and the type of damage that’s been observed in neurons affected by Parkinson’s,” said Lasmézas, senior author of the study. “Parkinson’s is a disorder of the mitochondria, and we discovered how Lewy bodies are releasing a partial break-down product that has a high tropism for the mitochondria and destroys their ability to produce energy.”
Lewy bodies were described a century ago, but it wasn’t until 1997 that scientists discovered they were made of clumps of a misfolded protein called α-synuclein. When it’s not misfolded, α-synuclein is thought to carry out functions related to the transmission of signals between neurons.
In the current study, Lasmézas and her team looked at cell cultures of neurons that were induced to accumulate fibrils made of misfolded α-synuclein, mimicking Lewy bodies in patients with Parkinson’s. They discovered that when α-synuclein fibrils are broken down, it often creates a smaller protein clump, which they named pα-syn* (pronounced “P-alpha-syn-star”).
“Sometimes the nerve cells can efficiently degrade the α-synuclein fibrils, but if they get overwhelmed, the degradation may be incomplete,” noted Lasmézas. “And it turns out that the result of that partial degradation, pα-syn*, is toxic.”
Dr. Diego Grassi, a research associate in Lasmézas’ lab, made this discovery by labeling the pα-syn* with an antibody so he could follow it throughout the cell after it was created. He observed that pα-syn* traveled and attached itself to the mitochondria. Further investigation revealed that once the pα-syn* attached, the mitochondria began to break down. Researchers followed up with an analysis of mouse and human brain samples. They confirmed the existence of pα-syn* in the dopamine-producing neurons.
“The Lewy bodies are big aggregates and they’re sitting in the cell, but they don’t come into direct contact with the mitochondria in the way pα-syn* does,” Lasmézas explained. “With Diego’s discovery, we’ve made a direct connection between the protein α-synuclein and the downstream effects that are observed when brain cells become damaged in Parkinson’s. What we found may not be the only mechanism of toxicity, but we know it’s important. This paper is about identifying where pα-syn* comes from and what it does to the mitochondria, but there’s obviously, mechanistically, a lot that we still don’t know.”
Lasmézas pointed out that these findings also have implications for designing treatments for Parkinson’s, noting that some drugs currently under development are focused on getting rid of larger fibrils that make up Lewy bodies. “It’s important to be aware that when Lewy bodies are broken down, these toxic substances may be created,” Lasmézas said. She added that the discovery of pα-syn* as an important component of the disease process points to a new target for creating drugs that could slow disease progression.
Scientists from TSRI have also discovered a new target for treating major depressive disorder, a disease which affects more than 16 million American adults. The research shows that individuals with high levels of a GPR158 receptor may be more susceptible to depression following chronic stress.
“The next step in this process is to come up with a drug that can target this receptor,” said Dr. Kirill Martemyanov, co-chair of the TSRI Department of Neuroscience at the Florida campus and senior author of the new study, which was published recently in eLife.
The researchers have said there is an urgent need for new drug targets in major depressive disorder. Current pharmacological treatments for depression can take a month or more to start working, and they don’t work in all patients. “We need to know what is happening in the brain so that we can develop more efficient therapies,” remarked Dr. Cesare Orlandi, senior research associate at TSRI and co-first author of the study.
Researchers zeroed in on GPR158 after discovering that the protein is elevated in people with major depressive disorder. To better understand GPR158’s role, the scientists studied male and female mice with and without GPR158 receptors. Behavioral tests revealed that both male and female mice with elevated GPR158 showed signs of depression following chronic stress. Conversely, suppression of GPR158 protected mice from developing depressive-like behaviors and made them resilient to stress.
The research team demonstrated that GPR158 affects key signaling pathways involved in mood regulation in the region of the brain called prefrontal cortex, though the researchers emphasized that the exact mechanisms remain to be established. Martemyanov explained that GPR158 is an orphan receptor with a poorly understood biology and mechanism of action. GPR158 appears to work downstream from other important brain systems, such as the GABA, a major player in the brain’s inhibitory control and adrenergic system involved in stress effects. “This is really new biology, and we still need to learn a lot,” said Martemyanov.
The study offers potential insight into why some people are more susceptible to mental illness. Because mice without GPR158 don’t alter their behavior after chronic stress, the researchers concluded that GPR158-deficient mice were naturally more resilient against depression. Their genetics offer a layer of protection.
Dr. Laurie Sutton, a research associate at TSRI and co-first author of the study, noted that this finding matches what doctors have noticed in people who have experienced chronic stress. “There’s always a small population that is resilient—they don’t show the depressive phenotype,” said Sutton.
As the search goes on for additional targets for depression, Martemyanov noted that more scientists are using new tools in genome analysis to identify orphan receptors like GPR158. “Those are the untapped biology of our genomes, with significant potential for development of innovative therapeutics,” he concluded.