Scholars@Duke
Andrew Bradley West

Andrew Bradley West

Professor of Pharmacology and Cancer Biology
Pharmacology & Cancer Biology
andrew.west@duke.edu
MSRB III 5124, DUMC 103853, Durham, NC 27710
3 Genome Court, MSRB III 5th FL, Durham, NC 27710

Selected Publications

Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.

Journal Article Sci Adv · November 2024 The intricate process of α-synuclein aggregation and fibrillization holds pivotal roles in Parkinson's disease (PD) and multiple system atrophy (MSA). While mouse α-synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induc ... Full text Link to item Cite

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.

Journal Article Mol Neurodegener · June 11, 2024 BACKGROUND: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological res ... Full text Link to item Cite

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.

Journal Article bioRxiv · April 17, 2024 BACKGROUND: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological res ... Full text Link to item Cite

A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.

Journal Article medRxiv · January 18, 2024 BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and su ... Full text Link to item Cite

Anionic nanoplastic contaminants promote Parkinson's disease-associated α-synuclein aggregation.

Journal Article Sci Adv · November 15, 2023 Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity inte ... Full text Link to item Cite

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Journal Article Sci Transl Med · August 30, 2023 Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to en ... Full text Link to item Cite

The interplay between monocytes, α-synuclein and LRRK2 in Parkinson's disease.

Journal Article Biochem Soc Trans · April 26, 2023 The accumulation of aggregated α-synuclein in susceptible neurons in the brain, together with robust activation of nearby myeloid cells, are pathological hallmarks of Parkinson's disease (PD). While microglia represent the dominant type of myeloid cell in ... Full text Open Access Link to item Cite

Who to Enroll in Parkinson Disease Prevention Trials? The Case for Genetically At-Risk Cohorts.

Journal Article Neurology · August 16, 2022 Therapies that prevent the occurrence of Parkinson disease (PD) (primary prevention) or mitigate the progression of symptoms in those with early disease (secondary prevention) are a critical unmet need in disease management. Despite great promise, PD preve ... Full text Link to item Cite

Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease.

Journal Article Mov Disord · July 2022 BACKGROUND: Pathogenic leucine-rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. OBJECTIVES: Through me ... Full text Link to item Cite

Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain.

Journal Article Mol Neurodegener · January 10, 2022 BACKGROUND: Leucine rich repeat kinase 2 (LRRK2) and SNCA are genetically linked to late-onset Parkinson's disease (PD). Aggregated α-synuclein pathologically defines PD. Recent studies identified elevated LRRK2 expression in pro-inflammatory CD16+ monocyt ... Full text Link to item Cite

Evaluation of ABT-888 in the amelioration of α-synuclein fibril-induced neurodegeneration.

Journal Article Brain Commun · 2022 The accumulation of α-synuclein inclusions in vulnerable neuronal populations pathologically defines Lewy body diseases including Parkinson's disease. Recent pre-clinical studies suggest poly(ADP-ribose) polymerase-1 activation and the subsequent generatio ... Full text Link to item Cite

Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein.

Journal Article Acta Neuropathol Commun · November 8, 2021 Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson's Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majo ... Full text Link to item Cite

Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

Journal Article · October 5, 2021 AbstractPathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause o ... Full text Cite

Genetic background influences LRRK2-mediated Rab phosphorylation in the rat brain.

Journal Article Brain Res · May 15, 2021 Pathogenic missense mutations in the leucine-rich repeat kinase 2 gene, encoding LRRK2, results in the upregulation of Rab10 and Rab12 phosphorylation in different cells and tissues. Here, we evaluate levels of the LRRK2 kinase substrates pT73-Rab10 and pS ... Full text Link to item Cite

Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.

Journal Article Acta Neuropathol · May 2021 The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. W ... Full text Open Access Link to item Cite

Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson's disease cohort.

Journal Article Hum Mol Genet · April 30, 2021 Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well a ... Full text Link to item Cite

Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease.

Journal Article NPJ Parkinsons Dis · April 13, 2021 Increasing evidence supports the role of brain and systemic inflammation in the etiology of Parkinson disease (PD). We used gene expression profiling to examine the activation state of peripheral blood monocytes in 18 patients with early, untreated PD and ... Full text Link to item Cite

Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia.

Journal Article Acta Neuropathol · April 2021 α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced convers ... Full text Link to item Cite

Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.

Journal Article JAMA Netw Open · April 1, 2021 IMPORTANCE: Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been repo ... Full text Link to item Cite

Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation.

Journal Article Movement disorders : official journal of the Movement Disorder Society · January 2021 Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non ... Full text Cite

Exosome markers of LRRK2 kinase inhibition.

Journal Article NPJ Parkinsons Dis · November 13, 2020 Hyper-activated LRRK2 is linked to Parkinson's disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, maybe critical in the development of successful LRRK2-targeting therapeutics. In this study, two diff ... Full text Link to item Cite

LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.

Journal Article EMBO J · October 15, 2020 Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary ... Full text Link to item Cite

Pharmacodynamic Biomarkers for Emerging LRRK2 Therapeutics

Journal Article Frontiers in Neuroscience · August 6, 2020 Genetic studies have identified variants in the LRRK2 gene as important components of Parkinson’s disease (PD) pathobiology. Biochemical and emergent biomarker studies have coalesced around LRRK2 hyperactivation in disease. Therapeutics that diminish LRRK2 ... Full text Cite

Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity.

Journal Article Proc Natl Acad Sci U S A · July 21, 2020 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a kinase and GTPase, and PD-linked mutations are known to influence both enzymatic acti ... Full text Link to item Cite

Parkinson disease and the immune system - associations, mechanisms and therapeutics.

Journal Article Nat Rev Neurol · June 2020 Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imagi ... Full text Link to item Cite

Pharmacodynamic Markers of LRRK2 Inhibition in Biofluids

Journal Article · 2020 Hyper-activated LRRK2 is linked to Parkinson’s disease susceptibility and progression. Quantitative measures of LRRK2 inhibition, especially in the brain, may be critical in the clinical development of successful LRRK2-targeting therapeutics. In this study ... Full text Cite

LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

Journal Article · 2020 Genetic variation in LRRK2 associates with susceptibility to Parkinson’s disease, Crohn’s disease, and mycobacteria infection, with high expression of LRRK2, and the LRRK2 kinase substrate Rab10, in phagocytic cells in the immune system. In mouse and human ... Full text Cite

Proteomic analysis of urinary extracellular vesicles reveal biomarkers for neurologic disease.

Journal Article EBioMedicine · July 2019 BACKGROUND: Extracellular vesicles (EVs) harbor thousands of proteins that hold promise for biomarker development. Usually difficult to purify, EVs in urine are relatively easily obtained and have demonstrated efficacy for kidney disease prediction. Herein ... Full text Open Access Link to item Cite

Caught in the act: LRRK2 in exosomes.

Journal Article Biochem Soc Trans · April 30, 2019 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a frequent genetic cause of late-onset Parkinson's disease (PD) and a target for therapeutic approaches. LRRK2 protein can influence vesicle trafficking events in the cytosol, with action both ... Full text Link to item Cite

The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease.

Journal Article Eur J Neurosci · February 2019 Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein compo ... Full text Link to item Cite

The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition.

Journal Article Exp Neurol · November 2018 The G2019S mutation in LRRK2 is one of the most common known genetic causes of neurodegeneration and Parkinson disease (PD). LRRK2 mutations are thought to enhance LRRK2 kinase activity. Efficacious small molecule LRRK2 kinase inhibitors with favorable dru ... Full text Link to item Cite

Sensitivity and specificity of phospho-Ser129 α-synuclein monoclonal antibodies.

Journal Article J Comp Neurol · August 15, 2018 α-Synuclein (α-syn) is an abundant presynaptic protein that is the primary constituent of inclusions that define Lewy body diseases (LBDs). In these inclusions, α-syn is phosphorylated at the serine-129 residue. Antibodies directed to this phosphorylation ... Full text Link to item Cite

Finding useful biomarkers for Parkinson's disease.

Journal Article Sci Transl Med · August 15, 2018 The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact. ... Full text Link to item Cite

LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network.

Journal Article Hum Mol Genet · January 15, 2018 Human genetic studies implicate LRRK2 and RAB7L1 in susceptibility to Parkinson disease (PD). These two genes function in the same pathway, as knockout of Rab7L1 results in phenotypes similar to LRRK2 knockout, and studies in cells and model organisms demo ... Full text Link to item Cite

Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.

Journal Article Exp Neurol · December 2017 In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical mode ... Full text Link to item Cite

Elevated LRRK2 autophosphorylation in brain-derived and peripheral exosomes in LRRK2 mutation carriers.

Journal Article Acta Neuropathol Commun · November 22, 2017 Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease (PD). LRRK2 mutations increase LRRK2 kinase activities that may increase levels of LRRK2 autophosphorylation at serine 1292 (pS1292) and neurotoxicit ... Full text Link to item Cite

α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration.

Journal Article Acta Neuropathol Commun · November 21, 2017 Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII-expressing immune cells in the brain correlates with α-synuclein inclusions. However, the tim ... Full text Link to item Cite

Breathing new life into an old target: pulmonary disease drugs for Parkinson's disease therapy.

Journal Article Genome Med · October 19, 2017 Increases in α-synuclein protein expression are suspected to increase the risk of the development of Parkinson's disease (PD). A recent study has demonstrated that β2-adrenergic receptor (β2AR) agonists decrease histone acetylation in the α-synuclein gene ... Full text Link to item Cite

LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model.

Journal Article Mol Ther Nucleic Acids · September 15, 2017 No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibitio ... Full text Link to item Cite

α-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic Neurodegeneration.

Journal Article Neurobiol Dis · September 2017 Proteinaceous inclusions in neurons, composed primarily of α-synuclein, define the pathology in several neurodegenerative disorders. Neurons can internalize α-synuclein fibrils that can seed new inclusions from endogenously expressed α-synuclein. The facto ... Full text Link to item Cite

Biochemical characterization of purified mammalian ARL13B protein indicates that it is an atypical GTPase and ARL3 guanine nucleotide exchange factor (GEF).

Journal Article J Biol Chem · June 30, 2017 Primary cilia play central roles in signaling during metazoan development. Several key regulators of ciliogenesis and ciliary signaling are mutated in humans, resulting in a number of ciliopathies, including Joubert syndrome (JS). ARL13B is a ciliary GTPas ... Full text Link to item Cite

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program.

Journal Article Biomark Med · May 2017 Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Dis ... Full text Link to item Cite

The dual enzyme LRRK2 hydrolyzes GTP in both its GTPase and kinase domains in vitro.

Journal Article Biochim Biophys Acta Proteins Proteom · March 2017 The evolutionarily conserved enzyme encoded by the leucine-rich repeat kinase 2 gene, LRRK2, harbors both a Rab-like GTPase domain and a serine/threonine protein kinase domain. Pathogenic mutations in either the GTPase or kinase domain can cause neurodegen ... Full text Link to item Cite

Exaggerated CpH methylation in the autism-affected brain.

Journal Article Mol Autism · 2017 BACKGROUND: The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the rol ... Full text Link to item Cite

LRRK2 levels in immune cells are increased in Parkinson's disease.

Journal Article NPJ Parkinsons Dis · 2017 Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells ... Full text Link to item Cite

Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease.

Journal Article Mov Disord · October 2016 BACKGROUND: Mutations in Leucine-rich repeat kinase 2 (LRRK2) enhance levels of the autophosphorylated LRRK2 protein and are the most common known cause of inherited Parkinson's disease (PD). LRRK2 has been further implicated in susceptibility to idiopathi ... Full text Link to item Cite

G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons.

Journal Article J Neurosci · July 13, 2016 UNLABELLED: Pathologic inclusions define α-synucleinopathies that include Parkinson's disease (PD). The most common genetic cause of PD is the G2019S LRRK2 mutation that upregulates LRRK2 kinase activity. However, the interaction between α-synuclein, LRRK2 ... Full text Link to item Cite

The NINDS Parkinson's disease biomarkers program.

Journal Article Mov Disord · June 2016 BACKGROUND: Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disea ... Full text Link to item Cite

Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.

Journal Article Transl Psychiatry · May 24, 2016 Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of ... Full text Link to item Cite

Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers.

Journal Article Neurology · March 15, 2016 OBJECTIVE: To test whether phosphorylated Ser-1292 LRRK2 levels in urine exosomes predicts LRRK2 mutation carriers (LRRK2+) and noncarriers (LRRK2-) with Parkinson disease (PD+) and without Parkinson disease (PD-). METHODS: LRRK2 protein was purified from ... Full text Link to item Cite

LRRK2 autophosphorylation enhances its GTPase activity.

Journal Article FASEB J · January 2016 The leucine-rich repeat kinase (LRRK)-2 protein contains nonoverlapping GTPase and kinase domains, and mutation in either domain can cause Parkinson disease. GTPase proteins are critical upstream modulators of many effector protein kinases. In LRRK2, this ... Full text Link to item Cite

14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.

Journal Article Hum Mol Genet · January 1, 2016 Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14 ... Full text Link to item Cite

M1 and M2 immune activation in Parkinson's Disease: Foe and ally?

Journal Article Neuroscience · August 27, 2015 Parkinson's Disease (PD) is a chronic and progressive neurodegenerative disorder of unknown etiology. Autopsy findings, genetics, retrospective studies, and molecular imaging all suggest a role for inflammation in the neurodegenerative process. However, re ... Full text Link to item Cite

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration.

Journal Article J Biol Chem · August 7, 2015 Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurod ... Full text Link to item Cite

The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins.

Journal Article Hum Mol Genet · August 1, 2015 The Leucine rich repeat kinase 2 (LRRK2) gene is genetically and biochemically linked to several diseases that involve innate immunity. LRRK2 protein is highly expressed in phagocytic cells of the innate immune system, most notably in myeloid cells capable ... Full text Link to item Cite

Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.

Journal Article Hum Mol Genet · July 15, 2015 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson's disease, and LRRK2 is also linked to Crohn's and Hansen's disease. LRRK2 is expressed in many organs in mammals but is particularly abundant i ... Full text Link to item Cite

Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic.

Journal Article Mov Disord · February 2015 The burden that Parkinson's disease (PD) exacts on the population continues to increase year after year. Though refinement of symptomatic treatments continues at a reasonable pace, no accepted therapies are available to slow or prevent disease progression. ... Full text Link to item Cite

Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.

Journal Article Mol Biol Cell · December 15, 2014 Aggregates of α-synuclein (α-syn) accumulate in neurons in Parkinson's disease and other synucleinopathies. These inclusions predominantly localize to axons even in the early stages of the disease, but their affect on axon function has remained unknown. Pr ... Full text Link to item Cite

Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism.

Journal Article Nat Commun · December 10, 2014 Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from ... Full text Link to item Cite

Unique functional and structural properties of the LRRK2 protein ATP-binding pocket.

Journal Article J Biol Chem · November 21, 2014 Pathogenic mutations in the LRRK2 gene can cause late-onset Parkinson disease. The most common mutation, G2019S, resides in the kinase domain and enhances activity. LRRK2 possesses the unique property of cis-autophosphorylation of its own GTPase domain. Be ... Full text Link to item Cite

PGC-1α provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.

Journal Article J Neurosci · October 22, 2014 Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1α in the brain ... Full text Link to item Cite

Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents.

Journal Article J Comp Neurol · August 1, 2014 Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of late-onset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. ... Full text Link to item Cite

Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats.

Journal Article Proc Natl Acad Sci U S A · June 24, 2014 Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease. Past studies have provided conflicting evidence for the protective effects of LRRK2 knockdown in models of Parkinson disease as well as other disord ... Full text Link to item Cite

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells.

Journal Article Neurobiol Dis · February 2014 Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, altho ... Full text Link to item Cite

RNA-Seq optimization with eQTL gold standards.

Journal Article BMC Genomics · December 17, 2013 BACKGROUND: RNA-Sequencing (RNA-Seq) experiments have been optimized for library preparation, mapping, and gene expression estimation. These methods, however, have revealed weaknesses in the next stages of analysis of differential expression, with results ... Full text Link to item Cite

LRRK2 secretion in exosomes is regulated by 14-3-3.

Journal Article Hum Mol Genet · December 15, 2013 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) ... Full text Link to item Cite

Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies.

Journal Article Biochem J · July 1, 2013 Missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a major cause of PD (Parkinson's disease). Several antibodies against LRRK2 have been developed, but results using these polyclonal antibodies have varied widely leading to conflicting conclusi ... Full text Link to item Cite

Defining the contribution of CNTNAP2 to autism susceptibility.

Journal Article PLoS One · 2013 Multiple lines of genetic evidence suggest a role for CNTNAP2 in autism. To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 1 ... Full text Link to item Cite

Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape.

Journal Article Genome Biol · 2013 BACKGROUND: DNA methylation is an epigenetic modification that changes with age in human tissues, although the mechanisms and specificity of this process are still poorly understood. We compared CpG methylation changes with age across 283 human blood, brai ... Full text Link to item Cite

Basal Ganglia Disorders

Chapter · January 1, 2013 Full text Cite

LRRK2 inhibition attenuates microglial inflammatory responses.

Journal Article J Neurosci · February 1, 2012 Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), and common genetic variation in LRRK2 modifies susceptibility to Crohn's disease and leprosy. High levels of LRRK2 expression in peripheral monocytes and ... Full text Link to item Cite

Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations.

Journal Article PLoS One · 2012 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of autosomal dominant familial Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing GTPase and kinase enzymatic domains. Disease-associated mutations in LRRK ... Full text Link to item Cite

GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.

Journal Article PLoS Genet · 2012 Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 encodes a large multi-domain protein with GTPase and kinase activity. I ... Full text Link to item Cite

Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities.

Journal Article J Mol Biol · September 9, 2011 The leucine-rich repeat kinase 2 (LRRK2) protein has both guanosine triphosphatase (GTPase) and kinase activities, and mutation in either enzymatic domain can cause late-onset Parkinson disease. Nucleotide binding in the GTPase domain may be required for k ... Full text Link to item Cite

Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death.

Journal Article Nat Med · June 2011 Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a ... Full text Link to item Cite

Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas.

Journal Article Proc Natl Acad Sci U S A · January 25, 2011 The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, hepatocyte growth factor (HGF). We sou ... Full text Link to item Cite

Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif.

Journal Article PLoS One · October 27, 2010 Mutations in LRRK2 (leucine-rich repeat kinase 2) have been identified as major genetic determinants of Parkinson's disease (PD). The most prevalent mutation, G2019S, increases LRRK2's kinase activity, therefore understanding the sites and substrates that ... Full text Link to item Cite

Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease.

Journal Article Mov Disord · October 15, 2010 Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) tha ... Full text Link to item Cite

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.

Journal Article Nat Med · September 2010 Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2- ... Full text Link to item Cite

Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization.

Journal Article J Biol Chem · December 25, 2009 Dominant missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson disease. LRRK2 encodes a serine/threonine protein kinase, and pathogenic mutations may increase kinase activity. Intrinsic GTP ... Full text Link to item Cite

Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease.

Journal Article Nat Cell Biol · November 2009 Mutations of the ubiquitin ligase parkin account for most autosomal recessive forms of juvenile Parkinson's disease (AR-JP). Several studies have suggested that parkin possesses DNA-binding and transcriptional activity. We report here that parkin is a p53 ... Full text Link to item Cite

LRRK2 in Parkinson's disease: function in cells and neurodegeneration.

Journal Article FEBS J · November 2009 The detailed characterization of the function of leucine-rich repeat kinase 2 (LRRK2) may provide insight into the molecular basis of neurodegeneration in Parkinson's disease (PD) because mutations in LRRK2 cause a phenotype with strong overlap to typical ... Full text Link to item Cite

A genome-wide linkage and association scan reveals novel loci for autism.

Journal Article Nature · October 8, 2009 Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very ... Full text Link to item Cite

The therapeutic potential of LRRK2 and alpha-synuclein in Parkinson's disease.

Journal Article Antioxid Redox Signal · September 2009 Current treatments for Parkinson's disease fail to modify disease progression, and the underlying pathogenic mechanisms remain elusive. The identification of specific targets responsible for disease will aid in the development of relevant model systems and ... Full text Link to item Cite

Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease.

Journal Article Biochim Biophys Acta · July 2009 The frequency and potency of mutations in the LRRK2 gene redefine the role of genetic susceptibility in Parkinson's disease. Dominant missense mutations that fulfill initial criteria for potential gain of function mechanisms coupled with enzymatic activity ... Full text Link to item Cite

Parkin mediates the degradation-independent ubiquitination of Hsp70.

Journal Article J Neurochem · June 2008 Mutations in the parkin gene cause autosomal recessive, juvenile-onset parkinsonism. Parkin is an E3 ubiquitin ligase that mediates the ubiquitination of protein substrates. Disease-associated mutations cause a loss-of-function of parkin which may compromi ... Full text Link to item Cite

Dynamic and redundant regulation of LRRK2 and LRRK1 expression.

Journal Article BMC Neurosci · November 28, 2007 BACKGROUND: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene account for a significant proportion of autosomal-dominant and some late-onset sporadic Parkinson's disease. Elucidation of LRRK2 protein function in health and disease provides an ... Full text Link to item Cite

Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain.

Journal Article Brain Res · June 25, 2007 Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution o ... Full text Link to item Cite

Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.

Journal Article Hum Mol Genet · January 15, 2007 Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations in the LRRK2 gene initiate neurodegeneration remain unknown. Here, we dem ... Full text Link to item Cite

The role of PARKIN in parkinson’s disease

Chapter · January 1, 2007 Parkinson’s disease (PD) is the most common movement disorder and the second most common neurodegenerative disorder. Patients often present with heterogeneous symptoms, reflecting the underlying complex nature of pathogenesis (1). Prevalent motor-related s ... Cite

Localization of LRRK2 to membranous and vesicular structures in mammalian brain.

Journal Article Ann Neurol · November 2006 OBJECTIVE: The PARK8 gene responsible for late-onset autosomal dominant Parkinson's disease encodes a large novel protein of unknown biological function termed leucine-rich repeat kinase 2 (LRRK2). The studies herein explore the localization of LRRK2 in th ... Full text Link to item Cite

Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.

Journal Article Proc Natl Acad Sci U S A · December 20, 2005 Parkinson's disease (PD) is a disorder of movement, cognition, and emotion, and it is characterized pathologically by neuronal degeneration with Lewy bodies, which are cytoplasmic inclusion bodies containing deposits of aggregated proteins. Most PD cases a ... Full text Link to item Cite

Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.

Journal Article Proc Natl Acad Sci U S A · November 15, 2005 Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that LRRK2 mutations are the most common yet identified determinan ... Full text Link to item Cite

To die or grow: Parkinson's disease and cancer.

Journal Article Trends Neurosci · July 2005 Epidemiological evidence suggests a reduced incidence of many common types of non-smoking-related cancers in individuals with Parkinson's disease (PD). Genes that underlie familial forms of PD are often abnormally expressed in cancer, owing to their differ ... Full text Link to item Cite

Molecular pathophysiology of Parkinson's disease.

Book · 2005 Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. Although the etiology of PD is incompletely understood, the recent discovery of genes assoc ... Full text Link to item Cite

N-myc regulates parkin expression.

Journal Article J Biol Chem · July 9, 2004 Mutations in the parkin gene are common in early-onset and familial Parkinson's disease (PD), and the parkin protein interacts in the ubiquitin-proteasome system as an E3 ligase. However, the regulatory pathways that govern parkin expression are unknown. I ... Full text Link to item Cite

Genetics of parkin-linked disease.

Journal Article Hum Genet · March 2004 Research into Parkinson's disease (PD), once considered the archetypical non-genetic neurodegenerative disorder, has been revolutionized by the identification of a number of genes, mutations of which underlie various familial forms of the disease. Whereas ... Full text Link to item Cite

Parkin-proven disease: common founders but divergent phenotypes.

Journal Article Neurology · May 27, 2003 OBJECTIVE: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Delta40) to search for evidence of a common founder. METHOD: Clinical review, parkin gene sequencing, dosage ... Full text Link to item Cite

Parkin is not regulated by the unfolded protein response in human neuroblastoma cells.

Journal Article Neurosci Lett · May 1, 2003 Mutations in the parkin gene cause the majority of cases of familial-linked Parkinson's disease, and mounting evidence suggests that parkin may play a role in idiopathic disease. Previous reports suggest that parkin may respond to and relieve, via E3-ligas ... Full text Link to item Cite

Identification of a novel gene linked to parkin via a bi-directional promoter.

Journal Article J Mol Biol · February 7, 2003 Mutations of the parkin gene on chromosome 6q25-27 are the predominant genetic cause of early-onset and autosomal recessive juvenile parkinsonism. Parkin is a multi-domain protein with ubiquitin-protein E3 ligase activity that has a role in the proteasome- ... Full text Link to item Cite

Identification of a novel gene linked to Parkin via a bidirectional promoter

Conference Annals of the New York Academy of Sciences · January 1, 2003 Full text Cite

Functional association of the parkin gene promoter with idiopathic Parkinson's disease.

Journal Article Hum Mol Genet · October 15, 2002 Loss-of-function mutations in the parkin gene were first identified in autosomal recessive juvenile parkinsonism (AR-JP). Subsequently, parkin mutations were found in many early-onset patients with Parkinson's disease (PD) (<45 years at onset). We hypothes ... Full text Link to item Cite

Complex relationship between Parkin mutations and Parkinson disease.

Journal Article Am J Med Genet · July 8, 2002 Mutations in the Parkin gene cause juvenile and early onset Parkinsonism. While Parkin-related disease is presumed to be an autosomal-recessive disorder, cases have been reported where only a single Parkin allele is mutated and raise the possibility of a d ... Full text Link to item Cite

Clinical, 18F-dopa PET, and genetic analysis of an ethnic Chinese kindred with early-onset parkinsonism and parkin gene mutations.

Journal Article Mov Disord · July 2002 We report on clinical (18)F-labeled 6-fluorodopa ((18)F-dopa) positron emission tomography (PET) and molecular genetic analyses of an ethnic Chinese family in which three siblings presented with early-onset Parkinson's disease. As described in some parkin ... Full text Link to item Cite

Identification and characterization of the human parkin gene promoter.

Journal Article J Neurochem · September 2001 Compound mutations and homozygous loss of function of the parkin gene causes juvenile and early onset, autosomal recessive parkinsonism. Pathologically, the disease is associated with loss of dopaminergic neurons in the substantia nigra pars compacta and l ... Full text Link to item Cite

Refinement of the PARK3 locus on chromosome 2p13 and the analysis of 14 candidate genes.

Journal Article Eur J Hum Genet · September 2001 Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity, resting tremor and postural instability resulting from the deficiency of dopamine in the nigrostriatal system. Previously we mapped a suscepti ... Full text Link to item Cite

alpha-Synuclein gene haplotypes are associated with Parkinson's disease.

Journal Article Hum Mol Genet · August 15, 2001 We report haplotype analysis of the alpha-synuclein gene in Parkinson's disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and ... Full text Link to item Cite