Valina L. Dawson

The spread of prion‐like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion‐like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte‐activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons …

Grip Strength Page 1 protocols.io | https://dx.doi.org/10.17504/protocols.io.3byl4qmoovo5/v1 March 14, 2024 1/3 Mar 14, 2024 Grip Strength DOI dx.doi.org/10.17504/protocols.io.3byl4qmoovo5/v1 Xiaobo Mao , Ramhari Kumbhar , Hanseok Ko , Valina L. Dawson , Ted Dawson Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of …

Calcium ions serve as key intracellular signals. Local, transient increases in calcium concentrations can activate calcium sensor proteins that in turn trigger downstream effectors. In neurons, calcium transients play a central role in regulating neurotransmitter release and synaptic plasticity. However, it is challenging to capture the molecular events associated with these localized and ephemeral calcium signals. Here we present an engineered biotin ligase that generates permanent molecular traces in a calcium-dependent manner. The enzyme, calcium-dependent BioID (Cal-ID), biotinylates nearby proteins within minutes in response to elevated local calcium levels. The biotinylated proteins can be identified via mass spectrometry and visualized using microscopy. In neurons, Cal-ID labeling is triggered by neuronal activity, leading to prominent protein biotinylation that enables transcription-independent activity …

Used to assess nigrostriatal sensorimotor function in mice. Based on the Deacon 2006 protocol.

The Cylinder test is used to evaluate locomotor asymmetry and spontaneous movement in rodent models.

Objective To overcome proteostatic barriers and ameliorate Parkinson disease (PD) pathogenesis, we sought to determine whether knockdown of MTMR5 facilitates alpha-synuclein (asyn) turnover and rescues asyn proteotoxicity. Background PD is a neurodegenerative movement disorder marked by progressive motor and non-motor symptoms that lead to profound disability. Neurodegeneration in PD relates to toxic aggregation of asyn, and mounting evidence shows that asyn can be degraded through the conserved pathway of autophagy. However, multiple aspects of autophagy are impaired in PD, and available methods to modulate autophagy fail to confer clinical benefits in patients because of the intrinsic resistance of neurons to these methods. This resistance stems in part from MTMR5 (myotubularin-related phosphatase 5), a potent autophagy regulator that we previously identified to be selectively enriched …

Interspecies chimeras offer great potential for regenerative medicine and the creation of human disease models. Whether human pluripotent stem cell–derived neurons in an interspecies chimera can differentiate into functional neurons and integrate into host neural circuity is not known. Here, we show, using Engrailed 1 (En1) as a development niche, that human naive-like embryonic stem cells (ESCs) can incorporate into embryonic and adult mouse brains. Human-derived neurons including tyrosine hydroxylase (TH)+ neurons integrate into the mouse brain at low efficiency. These TH+ neurons have electrophysiologic properties consistent with their human origin. In addition, these human-derived neurons in the mouse brain accumulate pathologic phosphorylated α-synuclein in response to α-synuclein preformed fibrils. Optimization of human/mouse chimeras could be used to study human neuronal differentiation …

Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non‐motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)‐ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long‐term treatment …