Biology subjects

Conlon, M.

Publications and source records attributed to Conlon, M..

5 recordsLinked to original sources

bioRxiv2025

Ventral tegmental area dopamine controls timing variability

Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinsons disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start-related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine-depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.

neuroscience↗

bioRxiv2024

Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential

Non-muscle myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal synaptic plasticity, has substantial therapeutic potential. However, translating this potential to in vivo use has been hampered by the lack of selective tools. The most prototypical non-selective inhibitor, blebbistatin inactivates both NMII and cardiac myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that improve tolerability by selectively targeting NMII over CMII, including MT-228, which has excellent properties such as high brain penetration and efficacy in preclinical models of stimulant use disorder, which has no current FDA-approved therapies. The structure of MT-228 bound to myosin II provides insight into its 17-fold selectivity for NMII over CMII. MT-228s broad therapeutic window opens the door to new disease treatments and provides valuable tools for the scientific community, along with promising leads for future medication development. HighlightsO_LIResearch suggests numerous indications, from axon regeneration and cancer, would benefit from a small molecule inhibitor of non-muscle myosin II, a molecular motor that regulates the actin cytoskeleton. C_LIO_LICurrent chemical probe options are very limited and lack sufficient safety for in vivo C_LIO_LIstudies, which we show is primarily due to potent inhibition of cardiac myosin II. C_LIO_LIRational design that focused on improving target selectivity over the pan-myosin II inhibitor, blebbistatin, led to the identification of MT-228, a small molecule inhibitor with a wide therapeutic window. C_LIO_LIHigh-resolution structure of MT-228 bound to myosin II reveals that selectivity results from a different positioning compared to blebbistatin and an important sequence difference between cardiac and non-muscle myosin II in the inhibitor binding pocket. C_LIO_LIA single administration of MT-228 shows long-lasting efficacy in animal models of stimulant use disorder, a current unmet and rapidly escalating need with no FDA-approved treatments. C_LI

cell biology↗

bioRxiv2021

Cortical alpha-synuclein preformed fibrils do not affect interval timing in mice

One hallmark feature of Parkinsons disease (PD) is Lewy body pathology associated with misfolded alpha-synuclein. Previous studies have shown that striatal injection of alpha-synuclein preformed fibrils (PFF) can induce misfolding and aggregation of native alpha-synuclein in a prion-like manner, leading to cell death and motor dysfunction in mouse models. Here, we tested whether alpha-synuclein PFFs injected into the medial prefrontal cortex results in cognitive deficits in mouse models as measured by interval timing, which is reliably disrupted in PD patients and in rodent models. We injected human alpha-synuclein PFF or monomers in the medial prefrontal cortex pre-injected with adeno-associated virus (AAV) overexpressing human alpha-synuclein. Despite notable medial prefrontal cortical synucleinopathy, we did not observe consistent deficits in fixed-interval timing. These results suggest that cortical alpha-synuclein does not reliably disrupt interval timing in rodent models. HighlightsCortical injection of alpha-synuclein preformed fibrils (PFF) induces diffuse synucleinopathy Cortical injection of PFFs does not affect interval timing in mice Medial prefrontal cortical synucleinopathy does not reliably disrupt interval timing

neuroscience↗

bioRxiv2020

Discovery of a Novel, Selective and Short-Acting Skeletal Myosin II Inhibitor

Myosin IIs, actin-based motors that utilize the chemical energy of ATP to generate force, have potential as therapeutic targets. Their heavy chains differentiate the family into muscle (skeletal [SkMII], cardiac, smooth) and nonmuscle myosin IIs. Despite therapeutic potential for muscle disorders, no SkMII-specific inhibitor has been reported and characterized. Here we present the discovery, synthesis and characterization of "skeletostatins", novel derivatives of the pan-myosin II inhibitor blebbistatin, with selectivity within the myosin IIs for SkMII. In addition, the skeletostatins bear improved potency, solubility and photostability, without cytotoxicity. Based on its optimal in vitro profile, Skeletostatin 1s in vivo tolerability, efficacy and pharmacokinetics were determined. Skeletostatin 1 was well-tolerated in mice, impaired motor performance, and had an excellent muscle to plasma ratio. Skeletostatins are useful probes for basic research and a strong starting point for drug development.

pharmacology and toxicology↗

bioRxiv2019

A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators

Cell death can be executed by regulated apoptotic and non-apoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using live-cell, time-lapse imaging, and a library of 1,833 small molecules including FDA-approved drugs and investigational agents, we assemble a large compendium of kinetic cell death modulatory profiles for inducers of apoptosis and ferroptosis. From this dataset we identified dozens of small molecule inhibitors of ferroptosis, including numerous investigational and FDA-approved drugs with unexpected off-target antioxidant or iron chelating activities. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, were on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms linking amino acid levels to the regulation of ferroptosis sensitivity in cancer cells. These results highlight widespread bioactive compound pleiotropy and link amino acid sensing to the regulation of ferroptosis.

systems biology↗