Systems Biology   |   Personalized Neurology

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Systems Biology


Nat Neurosci. 2018;21:1482-1492

Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease.
Dong X, Liao Z, Gritsch D, Hadzhiev Y, Bai Y, Locascio JJ, Guennewig B, Liu G1, Blauwendraat C, Wang T, Adler CH, Hedreen JC, Faull RLM, Frosch MP, Nelson PT, Rizzu P, Cooper AA, Heutink P, Beach TG, Mattick JS, Müller F, Scherzer CR

Precision Neurology Program, Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA
Advanced Center for Parkinson's Disease Research of Harvard Medical School and Brigham & Women's Hospital, Boston, MA, USA


Enhancers function as DNA logic gates and may control specialized functions of billions of neurons. Here we show a tailored program of noncoding genome elements active in situ in physiologically distinct dopamine neurons of the human brain. We found 71,022 transcribed noncoding elements, many of which were consistent with active enhancers and with regulatory mechanisms in zebrafish and mouse brains. Genetic variants associated with schizophrenia, addiction, and Parkinson's disease were enriched in these elements. Expression quantitative trait locus analysis revealed that Parkinson's disease-associated variants on chromosome 17q21 cis-regulate the expression of an enhancer RNA in dopamine neurons. This study shows that enhancers in dopamine neurons link genetic variation to neuropsychiatric traits.

PMID: 30224808 PMCID: PMC6334654 DOI:10.1038/s41593-018-0223-0


figure 4

Sci Transl Med. 2010 Oct 6;2(52):52ra73. doi: 10.1126/scitranslmed.3001059.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.
Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropoulos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR; Global PD Gene Expression (GPEX) Consortium.

Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 65 Landsdowne Street, Suite 307A, Cambridge, MA 02139, USA.


Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.

Comment in
Neurobiology: Powerless against Parkinson's
[Nature, 2010]

PMID: 20926834 [PubMed - indexed for MEDLINE] PMCID: PMC3129986
Free PMC Article



Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10907-12. doi: 10.1073/pnas.0802437105. Epub 2008 Jul 31.

GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein.
Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC, Ney PA, Ng J, McGoldrick M, Mollenhauer B, Bresnick EH, Schlossmacher MG.

Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA.


Increased alpha-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD). Variation in SNCA expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We show that SNCA and the heme metabolism genes ALAS2, FECH, and BLVRB form a block of tightly correlated gene expression in 113 samples of human blood, where SNCA naturally abounds (validated P = 1.6 x 10(-11), 1.8 x 10(-10), and 6.6 x 10(-5)). Genetic complementation analysis revealed that these four genes are co-induced by the transcription factor GATA-1. GATA-1 specifically occupies a conserved region within SNCA intron-1 and directly induces a 6.9-fold increase in alpha-synuclein. Endogenous GATA-2 is highly expressed in substantia nigra vulnerable to PD, occupies intron-1, and modulates SNCA expression in dopaminergic cells. This critical link between GATA factors and SNCA may enable therapies designed to lower alpha-synuclein production.

Comment in
Transcriptional regulation of alpha-synuclein: insights from blood
[Future Neurology, 2009]

PMID: 18669654 [PubMed - indexed for MEDLINE] PMCID: PMC2504800
Free PMC Article



Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6. doi: 10.1073/pnas.1104409108. Epub 2011 Oct 3.

Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse.
Hu Y, Chopra V, Chopra R, Locascio JJ, Liao Z, Ding H, Zheng B, Matson WR, Ferrante RJ, Rosas HD, Hersch SM, Scherzer CR.

Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA.


Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD.

Comment in
Does chromatin modulation provide the first wet biomarker for Huntington's disease? [Mov Disord. 2012]
Chromatin plasticity and the pathogenesis of Huntington disease. [Proc Natl Acad Sci U S A. 2011]

Comment in
Chromatin plasticity and the pathogenesis of Huntington disease
Proc Natl Acad Sci U S A, 2011

PMID: 21969577 [PubMed - indexed for MEDLINE] PMCID: PMC3193232
Free PMC Article



Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14164-9. doi: 10.1073/pnas.1009485107. Epub 2010 Jul 26.

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease.
Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.


Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid beta peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Abeta is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death.

PMID: 20660724 [PubMed - indexed for MEDLINE] PMCID: PMC2922576
Free PMC Article



Ann Neurol. 2013 Nov 16. doi: 10.1002/ana.24053. [Epub ahead of print]

Metallothioneins as dynamic markers for brain disease in lysosomal disorders.
Cesani M, Cavalca E, Macco R, Leoncini G, Terreni MR, Lorioli L, Furlan R, Comi G, Doglioni C, Zacchetti D, Sessa M, Scherzer CR, Biffi A.

San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, 20132, Milan, Italy; The Neurogenomics Laboratory, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA, 02139, USA.


Objective: To facilitate development of novel disease-modifying therapies for Lysosomal Storage Disorder (LSD) characterized by nervous system involvement such as Metachromatic Leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this goal we sought to identify blood transcripts associated with the progression of MLD. Methods: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative PCR platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in post-mortem patient brains and in mouse models representing six other LSDs. MT expression during disease progression and in response to specific treatment was evaluated in one of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules. Results: Metallothionein genes were significantly over-expressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Over-expression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation that are biochemical hallmarks of lysosomal storage diseases. Interpretation: Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs. ANN NEUROL 2013. © 2013 American Neurological Association.

Copyright © 2013 American Neurological Association.
PMID: 24242821 [PubMed - as supplied by publisher]



PLoS Genet. 2010 Jul 15;6(7):e1001026. doi: 10.1371/journal.pgen.1001026.

Lysosomal dysfunction promotes cleavage and neurotoxicity of tau in vivo.
Khurana V, Elson-Schwab I, Fulga TA, Sharp KA, Loewen CA, Mulkearns E, Tyynelä J, Scherzer CR, Feany MB.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.


Expansion of the lysosomal system, including cathepsin D upregulation, is an early and prominent finding in Alzheimer's disease brain. Cell culture studies, however, have provided differing perspectives on the lysosomal connection to Alzheimer's disease, including both protective and detrimental influences. We sought to clarify and molecularly define the connection in vivo in a genetically tractable model organism. Cathepsin D is upregulated with age in a Drosophila model of Alzheimer's disease and related tauopathies. Genetic analysis reveals that cathepsin D plays a neuroprotective role because genetic ablation of cathepsin D markedly potentiates tau-induced neurotoxicity. Further, generation of a C-terminally truncated form of tau found in Alzheimer's disease patients is significantly increased in the absence of cathepsin D. We show that truncated tau has markedly increased neurotoxicity, while solubility of truncated tau is decreased. Importantly, the toxicity of truncated tau is not affected by removal of cathepsin D, providing genetic evidence that modulation of neurotoxicity by cathepsin D is mediated through C-terminal cleavage of tau. We demonstrate that removing cathepsin D in adult postmitotic neurons leads to aberrant lysosomal expansion and caspase activation in vivo, suggesting a mechanism for C-terminal truncation of tau. We also demonstrate that both cathepsin D knockout mice and cathepsin D-deficient sheep show abnormal C-terminal truncation of tau and accompanying caspase activation. Thus, caspase cleavage of tau may be a molecular mechanism through which lysosomal dysfunction and neurodegeneration are causally linked in Alzheimer's disease.

PMID: 20664788 [PubMed - indexed for MEDLINE] PMCID: PMC2904797
Free PMC Article



Arch Neurol. 2004 Aug;61(8):1200-5.

Loss of apolipoprotein E receptor LR11 in Alzheimer disease.
Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ.

Department of Neurology, Emory University, Atlanta, Ga, USA.
Erratum in Arch Neurol. 2007 Apr;64(4):557.


BACKGROUND: Genetic, epidemiologic, and biochemical evidence suggests that apolipoprotein E, low-density lipoprotein receptors, and lipid metabolism play important roles in sporadic Alzheimer disease (AD).

OBJECTIVE: To identify novel candidate genes associated with sporadic AD.

DESIGN: We performed an unbiased microarray screen for genes differentially expressed in lymphoblasts of patients with sporadic AD and prioritized 1 gene product for further characterization in AD brain.

SETTING: Emory University, Atlanta, Ga.

SUBJECTS: Cell lines were used from 14 patients with AD and 9 normal human control subjects.

RESULTS: Six genes were differentially expressed in lymphoblasts of 2 independent groups of patients with probable AD and autopsy-proven AD. We hypothesized that 1 of the genes, termed low-density lipoprotein receptor relative with 11 binding repeats (LR11) (reduced 1.8- and 2.5-fold in AD lymphoblasts vs controls), might be associated with sporadic AD on the basis of its function as neuronal apolipoprotein E receptor. We found dramatic and consistent loss of immunocytochemical staining for LR11 in histologically normal-appearing neurons in AD brains. This reduction of LR11 protein was confirmed by quantitative Western blotting (P =.01).

CONCLUSIONS: There is loss of the microarray-derived candidate, LR11, in neurons of AD brains. This study shows that microarray analysis of widely available lymphoblasts derived from patients with AD holds promise as a primary screen for candidate genes associated with AD.

Comment in
Apolipoprotein E receptor LR11: intersections between neurodegeneration and cholesterol metabolism. [Arch Neurol. 2004]

PMID: 15313836 [PubMed - indexed for MEDLINE]

Comment in
Molecular biology. Trafficking protein suspected in Alzheimer's disease.
[Science, 2007]
PMID: 17234920 [PubMed - indexed for MEDLINE]

This is the first paper to implicate the SORL1/LR11 gene in Alzheimer’s that is now an unequivocally confirmed susceptibility locus.



Hum Mol Genet. 2003 Dec 15;12(24):3259-67. Epub 2003 Oct 21.

Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease.
Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C, Welsh-Bohmer KA.

Department of Medicine, Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center, Box 3445, Durham, NC 27710, USA.

Erratum in Hum Mol Genet. 2004 Mar 1;13(5):573.


We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

PMID: 14570706 [PubMed - indexed for MEDLINE]



Hum Mol Genet. 2003 Oct 1;12(19):2457-66. Epub 2003 Aug 5.

Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease.
Scherzer CR, Jensen RV, Gullans SR, Feany MB.

Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA 02139, USA.


Transgenic Drosophila expressing human alpha-synuclein faithfully replicate essential features of human Parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in alpha-synuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with alpha-synuclein expression. Most importantly, at the pre-symptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of alpha-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.

PMID: 12915459 [PubMed - indexed for MEDLINE]



Ann Neurol. 1997 Aug;42(2):265-9.

Frataxin gene of Friedreich's ataxia is targeted to mitochondria.
Priller J, Scherzer CR, Faber PW, MacDonald ME, Young AB.

Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.


Friedreich's ataxia is caused by a triplet repeat expansion in intron 1, a noncoding region of the frataxin gene (X25). We have generated a chimeric gene composed of the frataxin gene fused with the green fluorescent protein (GFP) gene as a reporter. Transfection of the fusion construct into living COS cells revealed that the frataxin-GFP construct localizes to organelles that double-label with 8-(4'-chloromethyl) phenyl-2,3,5,6,11,12,14,15-octahydro-1H,4H,10H-13H-diquinolizin o-8H-xanthylium chloride (CMXRos), a novel mitochondrial dye. Thus, frataxin appears to be a nuclear-encoded mitochondrial protein.

PMID: 9266741 [PubMed - indexed for MEDLINE]

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