Honors & Awards
Predoctoral Individual National Research Service Award (F31), National Institute of Health, NINDS (2016-2017)
BRAINS Fellow, University of Washington (2019)
Neuroscience Scholars Program Associate, Society for Neuroscience (2019-2020)
Boards, Advisory Committees, Professional Organizations
Co-Chair, Stanford SURPAS Diversity Advisory Committee (2019 - 2021)
Postdoc Representative, Stanford SOM Diversity Cabinet (2019 - 2021)
Doctor of Philosophy, University of Virginia (2018)
Bachelor of Science, Florida State University (2011)
Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain.
Activating LRRK2 mutations cause Parkinson's disease, and pathogenic LRRK2 kinase interferes with ciliogenesis. Previously, we showed that cholinergic interneurons of the dorsal striatum lose their cilia in R1441C LRRK2 mutant mice (Dhekne et al., 2018). Here, we show that cilia loss is seen as early as 10 weeks of age in these mice and also in two other mouse strains carrying the most common human G2019S LRRK2 mutation. Loss of the PPM1H phosphatase that is specific for LRRK2-phosphorylated Rab GTPases yields the same cilia loss phenotype seen in mice expressing pathogenic LRRK2 kinase, strongly supporting a connection between Rab GTPase phosphorylation and cilia loss. Moreover, astrocytes throughout the striatum show a ciliation defect in all LRRK2 and PPM1H mutant models examined. Hedgehog signaling requires cilia, and loss of cilia in LRRK2 mutant rodents correlates with dysregulation of Hedgehog signaling as monitored by in situ hybridization of Gli1 and Gdnf transcripts. Dopaminergic neurons of the substantia nigra secrete a Hedgehog signal that is sensed in the striatum to trigger neuroprotection; our data support a model in which LRRK2 and PPM1H mutant mice show altered responses to critical Hedgehog signals in the nigrostriatal pathway.
View details for DOI 10.7554/eLife.67900
View details for PubMedID 34658337
Locus coeruleus in memory formation and Alzheimer's disease.
The European journal of neuroscience
Catecholamine neurons of the locus coeruleus (LC) in the dorsal pontine tegmentum innervate the entire neuroaxis, with signaling actions implicated in the regulation of attention, arousal, sleep-wake cycle, learning, memory, anxiety, pain, mood, and brain metabolism. The co-release of norepinephrine (NE) and dopamine (DA) from LC terminals in the hippocampus plays a role in all stages of hippocampal-memory processing. This catecholaminergic regulation modulates the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. LC neurons in awake animals have two distinct firing modes: tonic firing (explorative) and phasic firing (exploitative). These two firing modes exert different modulatory effects on post-synaptic dendritic spines. In the hippocampus, the firing modes regulate long-term potentiation (LTP) and long-term depression, which differentially regulate the mRNA expression and transcription of plasticity-related proteins (PRPs). These proteins aid in structural alterations of dendritic spines, i.e., structural long-term potentiation (sLTP), via expansion and structural long-term depression (sLTD) via contraction of post-synaptic dendritic spines. Given the LC's role in all phases of memory processing, the degeneration of 50% of the LC neuron population occurring in Alzheimer's disease (AD) is a clinically relevant aspect of disease pathology. The loss of catecholaminergic regulation contributes to dysfunction in memory processes along with impaired functions associated with attention and task-completion. The multifaceted role of the LC in memory and general task performance and the close correlation of LC degeneration with neurodegenerative disease progression together implicate it as a target for new clinical assessment tools.
View details for DOI 10.1111/ejn.15045
View details for PubMedID 33190318
A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.
Neurobiology of aging
2020; 90: 125–34
A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons. The C9+ neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9+ neurons. Moreover, C9+ neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9+ neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
View details for DOI 10.1016/j.neurobiolaging.2020.02.011
View details for PubMedID 32184029
View details for PubMedCentralID PMC7166179
Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons.
2018; 136 (4): 589–605
α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.
View details for DOI 10.1007/s00401-018-1886-z
View details for PubMedID 29995210
View details for PubMedCentralID PMC6329667
mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease.
Alzheimer's & dementia : the journal of the Alzheimer's Association
2017; 13 (2): 152–67
A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.
View details for DOI 10.1016/j.jalz.2016.08.015
View details for PubMedID 27693185
View details for PubMedCentralID PMC5318248
Tau: The Center of a Signaling Nexus in Alzheimer's Disease.
Frontiers in neuroscience
2016; 10: 31
Tau is a microtubule-associated protein whose misfolding, hyper-phosphorylation, loss of normal function and toxic gain of function are linked to several neurodegenerative disorders, including Alzheimer's disease (AD). This review discusses the role of tau in amyloid-β (Aβ) induced toxicity in AD. The consequences of tau dysfunction, starting from the axon and concluding at somadendritic compartments, will be highlighted.
View details for DOI 10.3389/fnins.2016.00031
View details for PubMedID 26903798
View details for PubMedCentralID PMC4746348