Paula Desplats

• PhD
• Professor (Assistant) at University of California, San Diego

Metatranscriptome (MetaT) sequencing is a critical tool for profiling the dynamic metabolic functions of microbiomes. In addition to taxonomic information, MetaT also provides real-time gene expression data of both host and microbial populations, thus permitting authentic quantification of the functional (enzymatic) output of the microbiome and its...

Animals exhibit innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance responses. The posterolateral cortical amygdala (plCoA) mediates innate attraction and av...

Animals exhibit innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance responses. The posterolateral cortical amygdala (plCoA) mediates innate attraction and av...

Background Studies using Alzheimer’s disease (AD) models suggest that gut bacteria contribute to amyloid pathology and systemic inflammation. Further, gut‐derived metabolites serve critical roles in regulating cholesterol, blood‐brain barrier permeability, neuroinflammation, and circadian rhythms. Recent studies from the Alzheimer’s Disease Neuroim...

Animals perform innate behaviors that are stereotyped responses to specific evolutionarily relevant stimuli in the absence of prior learning or experience. These behaviors can be reduced to an axis of valence, whereby specific odors evoke approach or avoidance. The cortical amygdala (plCoA) mediates innate attraction and aversion to odor. However,...

Background Disruptions in circadian rhythm are a common symptom of Alzheimer’s disease (AD), which occur early in disease progression and may contribute to the neurodegenerative process. However, the mechanisms that link alterations in rhythmic transcription and disease pathology are poorly understood. Here we used brain‐wide spatial transcriptomic...

Circadian disruptions impact nearly all people with Alzheimer’s disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including...

Alzheimer's disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations in PSEN1, PSEN2, and APP, they do have a higher heritability (92-100%) than sporadic late-onset AD (LOAD, 70%) (Wingo et...

Alzheimer′s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver...

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagno...

Alzheimer’s disease (AD) manifested before 65 years of age is commonly referred to as early-onset AD (EOAD) [1]. Significant research on EOAD has focused on autosomal-dominant familial mutations in PSEN1 , PSEN2 , and APP ; however, these mutations only represent 5–10% of EOAD cases. Although EOAD has a higher heritability (92–100%) than sporadic l...

Background: Circadian rhythm disruptions impact nearly all Alzheimer's disease (AD) patients, with daytime sleepiness, sundowning, sleep fragmentation, and night-time insomnia being common disturbances. These early and progressive declines support the role of circadian dysfunction as a driver of AD pathology, hence the therapeutic potential of cir...

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients...

Introduction: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomark...

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative movement disorder that presents with prominent cognitive and psychiatric dysfunction. Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of HD, as well as other neurodegenerative and psychiatric disorders, and epigenetic alterations in the comp...

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (N...

We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial p...

Multiple systems atrophy (MSA) is a rare neurodegenerative disorder characterized by the accumulation of α-synuclein in glial cells and neurodegeneration in the striatum, substantia nigra, and cerebellum. Aberrant miRNA regulation has been associated with neurodegeneration, including alterations of specific miRNAs in brain tissue, serum, and cerebr...

Parkinson’s Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall pat...

In this review we present a concept that, despite mounting evidence, received little attention so far: susceptibility to adult neurodegenerative diseases may be programmed in utero and early postnatal preventive measures may reduce the risk. We delineate the key mechanisms and players mediating this phenomenon laying a foundation for preventive str...

Neuroinflammation is a common pathological correlate of HIV‐associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor‐expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)‐β, surveys for damaged neurons, and orchestrates microglial differentiation. TRE...

Insulin and its receptor are widely expressed in a variety of tissues throughout the body including liver, adipose tissue, liver and brain. The insulin receptor is expressed as two functionally distinct isoforms, differentiated by a single 12 amino acid exon. The two receptor isoforms, designated IR/A and IR/B, are expressed in a highly tissue and...

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). The HPA axis is a dynamic system regulating homeostasis, especially the stress r...

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). The HPA axis is a dynamic system regulating homeostasis, especially the stress r...

Synucleinopathies, neurodegenerative disorders with alpha-synuclein (α-syn) accumulation, are the second leading cause of neurodegeneration in the elderly, however no effective disease-modifying alternatives exist for these diseases. Multiple system atrophy (MSA) is a fatal synucleinopathy characterized by the accumulation of toxic aggregates of α-...

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients....

Introduction: Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are inco...

View largeDownload slide The mechanisms underlying the accumulation and propagation of α-synuclein in Parkinson's disease remain unclear. Wrasidlo et al. show that a novel compound designed in silico (NPT100-18A) reduces α-synuclein toxicity by altering the interaction of α-synuclein with the cell membrane. NPT100-18A reduces neurodegeneration in...

Unlabelled: Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid β (Aβ) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that α-synuclein (α-syn) also accumulates in the brains of pati...

Neuronal stem cell (NSC) grafts have been investigated as a potential neuro-restorative therapy in Parkinson’s disease (PD) but their use is compromised by the death of grafted cells. We investigated the use of Cerebrolysin (CBL), a neurotrophic peptide mixture, as an adjunct to NSC therapy in the α-synuclein (α-syn) transgenic (tg) model of PD. In...

Background HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by...

α-Synuclein (α-syn) has been implicated in neurological disorders with parkinsonism including Parkinson's Disease (PD) and Dementia with Lewy Body (DLB). Recent studies have shown α-syn oligomers released from neurons can propagate from cell-to-cell in a prion-like fashion exacerbating neurodegeneration. In this report, we examined the role of the...

Background: Deposition of α-synuclein and neuroinflammation are key pathological features of Parkinson's disease (PD). There is no cure for the disease; however, targeting the pathological features might be available to modulate the disease onset and progression. Hypoestoxide (HE) has been demonstrated as a NF-κB modulator, thereby acting as a pot...

The recent years have witnessed an exponential growth in the knowledge of epigenetic mechanisms, and piling evidence now links DNA methylation and histone modifications with a wide range of physiological processes from embryonic development to memory formation and behavior. Not surprisingly, deregulation of epigenetic modifications is associated wi...

Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a pe...

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has r...

Parkinson's disease and Dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein. Recently, single chain antibodies (scFV) have been developed against individual conformational species of α-syn. Unlike more traditional mAbs, these scFVs will not activate or be endocytosed by Fc receptors. For this study...

Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a pe...

Background In dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR...

Alzheimer's Disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of Aβ in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intra-cranial viral...

Alzheimer's disease (AD) is associated with the formation of toxic amyloid-β (Aβ)42 oligomers, and recent evidence supports a role for Aβ dimers as building blocks for oligomers. Molecular dynamics simulation studies have identified clans for the dominant conformations of Aβ42 forming dimers; however, it is unclear if a larger spectrum of dimers is...

Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identifica...

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a compone...

Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences. Methods: This was a case-control comparison of HIV-1 seropositive (HIV+) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified...

Background Parkinson's disease (PD) is a multifactorial disease where environmental factors act on genetically predisposed individuals. Although only 5% of PD manifestations are associated with specific mutations, majority of PD cases are of idiopathic origin, where environment plays a prominent role. Concurrent exposure to Paraquat (PQ) and Maneb...

Desplats. Generation of mThy1-LRRK2 (G2019S) transgenic mice model.

Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse mod...

Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterat...

Abnormal accumulation of α-synuclein is centrally involved in the pathogenesis of many disorders with Parkinsonism and dementia. Previous in vitro studies suggest that α-synuclein dysregulates intracellular calcium. However, it is unclear whether these alterations occur in vivo. For this reason, we investigated calcium dynamics in transgenic mice e...

Forkhead box protein p1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in central nervous system (CNS) development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 both in vitro and in vivo usi...

Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α-synuclein (α-syn) in the central nervous system. Aggregation of α-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms an...

It is now recognized that the cell-to-cell transmission of misfolded proteins such as α-synuclein contributes to the neurodegenerative phenotype in neurological disorders such as idiopathic Parkinson's disease, Dementia with Lewy bodies, and Parkinson's disease dementia. Thus, establishing cell-based models for the transmission of α-synuclein is of...

Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset...

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to res...

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to res...

The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of α-synuclein (α-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed α-syn m...

Hippocampal and caudate levels of mGluR5 in alpha-syn transgenic mice. (A–C) Representative images of mGluR5 immunoreactivity in the CA2/3 of the hippocampus of non-tg, PDGF-alpha-syn and mThy1-alpha-syn tg mice respectively, analyzed in (D). (E–G) Representative images of mGluR5 immunoreactivity in the caudate of non-tg, PDGF-alpha-syn and mThy1-a...

mGluR5 mRNA levels in Control, DLB and PD cases and alpha-syn transgenic mice. (A) Quantitative real-time PCR (qPCR) analysis of mGluR5 mRNA levels in Control, DLB and PD cases. (B) qPCR analysis of mGluR5 mRNA levels in non-tg, PDGF-alpha-syn tg and mThy1-alpha-syn tg mice. (0.27 MB TIF)

High-resolution, large-scale maps of alpha-syn and mGluR5 in alpha-syn transgenic mice. (A) Representative confocal image depicting localization of alpha-syn (green) and mGluR5 (red) immunoreactivity in an alpha-syn tg mouse brain - inset at higher magnification in the right panel. (B) Representative confocal image depicting localization of alpha-s...

Hippocampal and caudate levels of mGluR5 in Control, DLB and PD cases. (A–C) Representative images of mGluR5 immunoreactivity in the CA2/3 of the hippocampus from control, DLB and PD cases respectively, analyzed in (D). (E–G) Representative images of mGluR5 immunoreactivity in the caudate from control, DLB and PD cases respectively, analyzed in (H)...

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are neurodegenerative disorders of the aging population characterized by the abnormal accumulation of alpha-synuclein (alpha-syn). Previous studies have suggested that excitotoxicity may contribute to neurodegeneration in these disorders, however the underlying mechanisms and their relati...

J. Neurochem. (2010) 115, 748–758. Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, psychiatric, and cognitive abnormalities. In this present study, we tested whether abnormal motor behavior in a mouse model of HD, the R6/1 transgenic (Tg) mice, was associated with changes in cerebellar lipid composition...

Neurodegenerative disorders such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and Creutzfeldt-Jakob disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between prot...

Immunoblot analysis of α-syn levels and lysosomal markers in the brains of AD and DLB patients. Brain homogenates from the temporal cortex of non-demented controls, AD, and DLB patients were separated into membrane and cytosolic fractions, and 20 µg of each sample was subjected to gel electrophoresis. Immunoblots were probed with antibodies against...

Immunocytochemical and immunoblot characterization of lentivirus-mediated Atg7 over-expression and knockdown in a neuronal cell line. B103 neuronal cells on coverslips were infected with LV-Atg7 or LV-shAtg7, followed by fixation and immunolabeling with an antibody against Atg7, or lysis and immunoblot analysis with antibodies against Atg7 or Actin...

Immunoblot analysis of α-syn levels and lysosomal markers in the brains of APP tg and α-syn tg mice. Brain homogenates from non tg, APP tg, and α-syn tg mice were separated into membrane and cytosolic fractions, and 20 µg of each sample was subjected to gel electrophoresis. Immunoblots were probed with antibodies against α-syn, Cathepsin D, LC3 and...

Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by alpha-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in alpha-synuclein clearance might play an important role. For th...

Neuronal accumulation of alpha-synuclein and Lewy body formation are characteristic to many neurodegenerative diseases, including Parkinson's disease (PD). This Lewy pathology appears to spread throughout the brain as the disease progresses. Furthermore, recent studies showed the occurrence of Lewy pathology in neurons grafted into the brains of PD...

Cell proliferation of neural progenitors in the subventricular zone (SVZ) of Parkinson disease (PD) patients and animal models is decreased. It was previously demonstrated that the neurotransmitter dopamine modulates cell proliferation in the embryonic brain. The aim of the present study was to analyze whether oral treatment with the dopamine recep...

Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional o...

Molecular dynamics simulations of α-syn multimers with Aβ monomers and dimers. The 4 ns α-syn dimer and the 2 ns Aβ conformer were used for modeling all complexes. (A) Structural organization of one α-syn dimer complexed with one Aβ monomer. (B) Structural organization of one α-syn trimer complexed with two Aβ monomers. (C) Structural organization...

Molecular dynamics simulations showing the changes in Aβ secondary structure over time. The first time zero line shows the amino acid sequence of Aβ1–42, and the remaining lines depict the secondary structural characteristics. (0.86 MB TIF)

Molecular dynamics simulations of Aβ conformers at various time points. (A) Initial conformer; (B) 0.5 ns conformer; (C) 1.0 ns conformer; (D) 1.5 ns conformer; (E) 2.0 ns conformer; (F) 2.5 ns conformer; (G) 3.0 ns conformer; and (H) superimposed image showing all conformers in a composite image. (0.69 MB TIF)

Increased levels of α-syn multimers in the presence of Aβ under in vitro aggregating conditions. Freshly-solubilized recombinant α-syn (10 µM) and freshly-solubilized Aβ (5–20 µM) were incubated together at the indicated ratios for 24 hrs and analyzed by immunoblot. (A) Incubation of α-syn with Aβ promotes the formation of a 170-kDa oligomer of α-s...

Analysis of intracellular calcium levels in cells expressing α-syn and treated with Aβ. 293T cells were infected with lenti-vector or lenti-α-syn for two days and treated with 10 µM freshly-solubilized Aβ1–42 for 24 hrs, followed by treatment with calcium dye and analyzed by fluorescence microscopy and with a spectrophotomer. (A) Minimal calcium dy...

Transcriptional dysregulation has emerged as a central pathogenic mechanism in Huntington's disease (HD), which is associated with neuropathological changes predominantly in the striatum. Here we demonstrate that expression of Bcl11b (a.k.a. CTIP2), a transcription factor exhibiting highly-enriched localization in adult striatum, is significantly d...

Altered expression and mutations in alpha-synuclein (alpha-syn) have been linked to Parkinson's disease (PD) and related disorders. The neurological alterations in PD patients have been associated with degeneration of dopaminergic cells and other neuronal populations. Moreover, recent studies in murine models have shown that alterations in neurogen...

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta)...

We have explored genome-wide expression of genes related to glycobiology in exon 1 transgenic Huntington's disease (HD) mice using a custom-designed GLYCOv2 chip and Affymetrix microarray analyses. We validated, using quantitative real-time PCR, abnormal expression levels of genes encoding glycosyltransferases in the striatum of R6/1 transgenic mic...