Person: Scherzer, Clemens
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Scherzer
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Clemens
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Scherzer, Clemens
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Publication Metallothioneins as dynamic markers for brain disease in lysosomal disorders(BlackWell Publishing Ltd, 2014) Cesani, Martina; Cavalca, Eleonora; Macco, Romina; Leoncini, Giuseppe; Terreni, Maria Rosa; Lorioli, Laura; Furlan, Roberto; Comi, Giancarlo; Doglioni, Claudio; Zacchetti, Daniele; Sessa, Maria; Scherzer, Clemens; Biffi, AlessandraObjective: To facilitate development of novel disease-modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, 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 polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 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 overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression 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, which are biochemical hallmarks of lysosomal storage diseases. Interpretation Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.Publication Network Analysis Identifies SOD2 mRNA as a Potential Biomarker for Parkinson's Disease(Public Library of Science, 2014) Santiago, Jose A.; Scherzer, Clemens; Potashkin, Judith A.Increasing evidence indicates that Parkinson's disease (PD) and type 2 diabetes (T2DM) share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2), is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE). The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted.Publication MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration(2014) Cebrián, Carolina; Zucca, Fabio A.; Mauri, Pierluigi; Steinbeck, Julius A.; Studer, Lorenz; Scherzer, Clemens; Kanter, Ellen; Budhu, Sadna; Mandelbaum, Jonathan; Vonsattel, Jean P.; Zecca, Luigi; Loike, John D.; Sulzer, DavidSubsets of rodent neurons are reported to express major histocompatibilty complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression, and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell derived dopamine (DA) neurons. Catecholamine murine cultured neurons are more responsive to induction of MHC-I by gamma-interferon than other neuronal populations. Neuronal MHC-I is also induced by factors released from microglia activated by neuromelanin or alpha-synuclein, or high cytosolic DA and/or oxidative stress. DA neurons internalize foreign ovalbumin and display antigen derived from this protein by MHC-I, which triggers DA neuronal death in the presence of appropriate cytotoxic T-cells. Thus, neuronal MHC-I can trigger antigenic response, and catecholamine neurons may be particularly susceptible to T cell-mediated cytotoxic attack.Publication A Feed-Forward Circuit of Endogenous PGC-1α and Estrogen Related Receptor α Regulates the Neuronal Electron Transport Chain(Hindawi Publishing Corporation, 2016) Bakshi, Rachit; Mittal, Shuchi; Liao, Zhixiang; Scherzer, ClemensPeroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a central regulator of cellular and mitochondrial metabolism. Cellular bioenergetics are critically important in “energy-guzzling” neurons, but the components and wiring of the transcriptional circuit through which PGC-1α regulates the neuronal electron transport chain have not been established. This information may be vital for restoring neuronal bioenergetics gene expression that is compromised during incipient Parkinson's neuropathology and in aging-dependent brain diseases. Here we delineate a neuronal transcriptional circuit controlled by endogenous PGC-1α. We show that a feed-forward circuit of endogenous neuronal PGC-1α and the orphan nuclear estrogen-related receptor α (ERRα) activates the nuclear-encoded mitochondrial electron transport chain. PGC-1α not only trans-activated expression of ERRα, but also coactivated ERRα target genes in complexes I, II, IV, and V of the neuronal electron transport chain via association with evolutionary conserved ERRα promoter binding motifs. Chemical activation of this transcriptional program induced transcription of the neuronal electron transport chain. These data highlight a neuronal transcriptional circuit regulated by PGC-1α that can be therapeutically targeted for Parkinson's and other neurodegenerative diseases.Publication Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's(John Wiley and Sons Inc., 2016) Liu, Ganqiang; Boot, Brendon; Locascio, Joseph; Jansen, Iris E.; Winder‐Rhodes, Sophie; Eberly, Shirley; Elbaz, Alexis; Brice, Alexis; Ravina, Bernard; van Hilten, Jacobus J.; Cormier‐Dequaire, Florence; Corvol, Jean‐Christophe; Barker, Roger A.; Heutink, Peter; Marinus, Johan; Williams‐Gray, Caroline H.; Scherzer, Clemens; Scherzer, C.; Hyman, B.T.; Ivinson, A.J.; Trisini‐Lipsanopoulos, A.; Franco, D.; Burke, K.; Sudarsky, L.R.; Hayes, M.T.; Umeh, C.C.; Growdon, J.H.; Schwarzschild, M.A.; Hung, A.Y.; Flaherty, A.W.; Wills, A.‐M.; Mejia, N.I.; Gomperts, S.N.; Khurana, V.; Selkoe, D.J.; Yi, T.; Page, K.; Liao, Z.; Barker, R.; Foltynie, T.; Williams‐Gray, C.H.; Mason, S.; Winder‐Rhodes, S.; Breen, D.; Cummins, G.; Evans, J.; Corvol, J.‐C.; Brice, A.; Elbaz, A.; Mallet, A.; Vidailhet, M.; Bonnet, A.‐M.; Bonnet, C.; Grabli, D.; Hartmann, A.; Klebe, S.; Lacomblez, L.; Mangone, G.; Bourdain, F.; Brandel, J.‐P.; Derkinderen, P.; Durif, F.; Mesnage, V.; Pico, F.; Rascol, O.; Forlani, S.; Lesage, S.; Tahiri, K.; van Hilten, J.J.; Marinus, J.; Duong, K.; Dong, X.; Hutten, S.J.; Amr, S.S.; Shoulson, I.; Tanner, C.M.; Lang, A.E.; Nalls, M.A.Objective: We hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates. Methods: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance. Interpretation Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685Publication Defining the contribution of neuroinflammation to Parkinson’s disease in humanized immune system mice(BioMed Central, 2017) Manocha, Gunjan Dhawan; Floden, Angela Marie; Puig, Kendra Lynn; Nagamoto-Combs, Kumi; Combs, Colin Kelly; Scherzer, ClemensBackground: Reactive microglia have been associated with the histological changes that occur in Parkinson’s disease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson’s disease have not been fully defined. Results: In order to improve understanding of the role of neuroinflammation in Parkinson’s disease, we employed the MPTP injection model using humanized CD34+ mice along with age-matched C57BL/6 mice. NSG mice engrafted with hu-CD34+ hematopoietic stem cells were injected with MPTP to quantify cytokine changes, neuron loss, gliosis, and behavioral dysfunction. The mice were also treated with or without the calcineurin/NFAT inhibitor, FK506, to determine whether modulating the immune response could attenuate disease. MPTP injections produced impairment of motor performance, increased microgliosis, elevated brain cytokine levels, and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum of both humanized CD34+ mice and C57BL/6 mice with a strikingly different profile of human versus mouse cytokine elevations observed in each. Interestingly, FK506 injections significantly attenuated the MPTP-induced effects in the humanized CD34+ mice compared the C57BL/6 mice. In addition, analyses of human plasma from Parkinson’s disease donors compared to age-matched, healthy controls demonstrated an increase in a number of pro-inflammatory cytokines in female patients similar to that observed in MPTP-injected female CD34+ mice. Conclusions: This study demonstrates for the first time, induction of Parkinson’s disease-like symptoms in female humanized CD34+ mice using MPTP. The profile of cytokine changes in the serum and brains of the humanized CD34+ mice following MPTP injection differed significantly from that occurring in the more commonly used C57BL/6 strain of mice. Moreover, several cytokine elevations observed in the MPTP injected humanized CD34+ mice were similarly increased in plasma of PD patients suggesting that these mice offer the more relevant model for the inflammatory aspects of human disease. Consistent with this, the effects of MPTP on loss of tyrosine hydroxylase immunoreactivity, loss of motor strength, and increase in proinflammatory cytokines were attenuated using an immunosuppressant drug, FK506, in the humanized CD34+ but not the C57BL/6 mice. Collectively, these findings suggest that MPTP injected, humanized CD34+ mice represent a more accurate model for assessing inflammatory changes in PD.Publication Identification of genetic modifiers of age-at-onset for familial Parkinson’s disease(Oxford University Press, 2016) Hill-Burns, Erin M.; Ross, Owen A.; Wissemann, William T.; Soto-Ortolaza, Alexandra I.; Zareparsi, Sepideh; Siuda, Joanna; Lynch, Timothy; Wszolek, Zbigniew K.; Silburn, Peter A.; Mellick, George D.; Ritz, Beate; Scherzer, Clemens; Zabetian, Cyrus P.; Factor, Stewart A.; Breheny, Patrick J.; Payami, HaydehParkinson’s disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.Publication Lysosomal Dysfunction Promotes Cleavage and Neurotoxicity of Tau In Vivo(Public Library of Science, 2010) Khurana, Vikram; Elson-Schwab, Ilan; Fulga, Tudor Alexandru; Sharp, Katherine A.; Loewen, Carin A.; Mulkearns, Erin; Tyynelä, Jaana; Scherzer, Clemens; Feany, MelExpansion 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.