Catalog
ASAP is committed to accelerating the pace of discovery and informing a path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing. We’ve created this catalog to showcase the research outputs and tools developed by ASAP-funded programs.
Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in Parkinsonian mice
Publication: Subthalamic nucleus deep brain stimulation relieves many motor symptoms of Parkinson’s disease, but its underlying therapeutic mechanisms remain unclear. Here, authors used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice to get at that question. View original preprint.
Teams
Adaptor protein-3 produces synaptic vesicles that release phasic dopamine
The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.
Teams
M4-mediated cholinergic transmission is reduced in Parkinsonian mice and its restoration alleviates motor deficits and levodopa-induced dyskinesia
Preprint: Despite M4-receptors being thought to mediate anti-kinetic effects, restoring M4-receptor function partially rescued Parkinsonian balance and coordination deficits and limited the development of levodopa-induced dyskinetic behaviors, indicating that decreased M4-function contributed to circuit and motor dysfunctions in response to DA loss.
Teams
The role of α-synuclein in exocytosis
The pathogenesis of degeneration in Parkinson’s disease (PD) remains poorly understood but multiple lines of evidence have converged on the presynaptic protein α-synuclein (αsyn). αSyn regulates several cellular processes, however, its normal function remains poorly understood. In this review, the authors focus on its role in exocytosis.
Teams
Alterations in neurotransmitter co-release in Parkinson’s disease
This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson’s disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson’s disease.
Teams
Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson’s disease progression
This review covers recent conceptual advances in our basic understanding of the dopamine system – including our rapidly advancing knowledge of dopamine neuron heterogeneity – with special attention to their importance for understanding PD.
Teams
Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
Preprint: Parkinson’s disease is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. To address this question, the authors developed a chemogenetic (DREADD) mouse model to increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology.
Teams
Inhibition of indirect pathway activity causes abnormal decision-making in a mouse model of impulse control disorder in Parkinson’s disease
Preprint: In Parkinson’s disease (PD), loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits. Lack of coordination between direct and indirect neurons is implicated in the disease. Here, the authors developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task.
Teams
Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input
The authors explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson’s disease therapy characterized by involuntary movements. Findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.
Role of dopamine neuron activity in Parkinson’s disease pathophysiology
Here, the authors focus on evidence that the activity of dopamine neurons is altered in Parkinson’s disease (PD), either as a compensatory response to degeneration or as a result of circuit dynamics or pathologic proteins, based on available human data and studies in animal models of PD.
Teams
Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production
Preprint: The authors’results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
Teams
