Parkinson’s Disease (PD) is a central nervous system disorder which causes motor control issues. Current medications help improve the quality of life of those with Parkinson’s by relieving some symptoms, but do not prevent the progression of the disease. A key sign of PD is the formation of Lewy bodies in the striatum and substantia nigra. Lewy bodies are a result of protein aggregation in the brain and a major component of these Lewy bodies is the protein α-synuclein, which is known to undergo many post-translational modifications, one of which being SUMOylation. Small ubiquitin-like modifiers (SUMO) can post-translationally modify proteins affecting their function and stability in a process known as SUMOylation(1). SUMO specific proteases (SENPs) are enzymes which play a role in the de-conjugation of SUMO proteins, making the process of SUMOylation a reversible one(2). In this study, we test the possibility of applying the inhibition of SENPs as a potential treatment for Parkinson’s disease. We tested a natural SENP1 inhibitor, Momordin Ic and a chemical inhibitor, S2A, in PFF treated cells. We have found that both SENP inhibitors are efficacious in reducing cytotoxicity and increasing cell viability after PFF-induced stress. Our results strongly suggest the potential use of the SENP1 inhibitors, S2A and Momordin, as a therapeutic application for Parkinson’s disease.

SUMO Protease1 (SENP1) Inhibitor as a Potential Therapeutic for Parkinson’s Disease

Neurons and Astrocytes are two key components to our brain’s way of relaying information. When several neurons fire action potential at the same time it is called neuronal synchronizing. This is implicated in many neuronal functions that occur during development- synaptic plasticity, establishment of functional neural networks, as well as pathological conditions such as epileptic seizures. Preliminary data gathered by my lab showed that astrocyte-neuron interactions are important for development of neuronal synchronous activity in developing vertebrate brains. We focused primarily on the astrocytic model of G-Protein Coupled Receptors (GPCR)-mediate calcium induced calcium release (CICR). Our model proposes that CICR in astrocytes is controlled by mGluR1, a metabotropic glutamate receptor that leads to the release of glutamate. To demonstrate this we cultured primary astrocytes from optic tectum dissection as well as Human Embryonic Kidney (HEK) Cells . The HEK cells were transfected with melanopsin and GCaMP

An Optogenetic Approach To Understand Molecular Mechanisms of Astrocyte-​Neuron Interactions in the Development of Neuronal Synchrony

Different studies show that TDP-43 plays a major role in association with other neurological diseases, however, we want to test why TDP-43 is a major factor. We injected a mouse with TDP-43 and injected another mouse with Alzheimer's Disease. The two mice were watched for more than over a month now. We used the mice's pellets to conduct the different tests we ran. We sonicatied the different mice pellets for a 1 min 20 minutes with a 5 sec pulse and 5 sec off cycle. Once the sonication was done, we transferred the sonicated pellets to the centrifuge machine which ran for about 35 minutes. Other graduate students began to compare results from these batches of pellets to the others that they tested to see the difference or similarities. These results showed us that the Alzheimer's disease mouse model that we developed over expresses pathological tau and TDP-43.

TDP-43 Mice Model

Recognition of an α-helix and a complementary cleft are prevelant in many disease-relevant Protein-Protein Interactions (PPIs), and disruption of these PPIs is the focus of many drug discovery efforts. In the first part of our study, we used computational hot-spot analysis to illuminate critical residues in established PPIs involving an α-helix and a complementary cleft. In the second part of this research, we designed proteins to inhibit α-helix / complementary cleft PPIs involved in two distinct steps of the SARS-CoV-2 entry pathway. Previously, we have shown that helix-grafted proteins designed to mimic the HIV-1 gp41 C-peptide, inhibit an interaction involving HIV-1 gp41 N-peptide trimer, and gp41 C-peptide, resulting in the inhibition of HIV-1 entry in a live virus assay. Here, we used helix-grafted display to create novel proteins designed to inhibit two distinct steps in the SARS-CoV-2 entry pathway, which both rely on PPIs involving an α-helix and a complementary cleft. The design of these proteins, t

Targeting α-Helix-Dependent Protein-Protein Interactions In Two Steps of the SARS-CoV-2 Entry Pathway

At the neuromuscular junction, binding of acetylcholine to receptors on the muscle causes an increase in intracellular calcium, leading to muscle contraction. Levamisole is an agonist for acetylcholine receptors (AChR) which effectively produces time-dependent paralysis. A voltage gated calcium channel (egl-19) facilities the movement of calcium into the cell promoting muscle stimulation. This influx of calcium then stimulates the release of calcium from the sarcoplasmic reticulum through unc-68. Calcium is then transported from the cytosol to the extracellular space where it can bind to troponin and myosin. After this, a membrane ATPase (mca-3) works to restore proper intracellular calcium levels. Thus, we would expect that the loss of this calcium-ATPase would cause increased intracellular calcium and faster paralysis than the wild type. However, in the paralysis assay the opposite phenotype is observed. MCA-3 only removes a single calcium ion from the cytoplasm per molecule of ATP. On the other hand, sarcoplasmic reticulum calcium-ATPases (SERCA) work together with membrane ATPases to lower cytoplasmic calcium levels by bringing calcium back to the sarcoplasmic reticulum. SERCAs are much more efficient and are able to transport two calcium ions per ATP molecule used (Ingesi and De Meis 1989). We hypothesize that sca-1 mutants will be levamisole hypersensitive, while mca-3 and unc-68 will be resistant to levamisole compared to controls.

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SUMO Protease1 (SENP1) Inhibitor as a Potential Therapeutic for Parkinson’s Disease

An Optogenetic Approach To Understand Molecular Mechanisms of Astrocyte-Neuron Interactions in the Development of Neuronal Synchrony

TDP-43 Mice Model

Targeting α-Helix-Dependent Protein-Protein Interactions In Two Steps of the SARS-CoV-2 Entry Pathway

Impact of Calcium-ATPase Activity on Bioenergetic Failure in Hyper-stimulated C. elegans

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Underline digital video library

SUMO Protease1 (SENP1) Inhibitor as a Potential Therapeutic for Parkinson’s Disease

An Optogenetic Approach To Understand Molecular Mechanisms of Astrocyte-​Neuron Interactions in the Development of Neuronal Synchrony

TDP-43 Mice Model

Targeting α-Helix-Dependent Protein-Protein Interactions In Two Steps of the SARS-CoV-2 Entry Pathway

Impact of Calcium-ATPase Activity on Bioenergetic Failure in Hyper-stimulated C. elegans

Stay up to date with the latest Underline news!

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RESOURCES

An Optogenetic Approach To Understand Molecular Mechanisms of Astrocyte-Neuron Interactions in the Development of Neuronal Synchrony