Publications

2019

Li, Yedda, Yue Xu, Bruno A Benitez, Murtaza S Nagree, Joshua T Dearborn, Xuntian Jiang, Miguel A Guzman, et al. (2019) 2019. “Genetic Ablation of Acid Ceramidase in Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target.”. Proceedings of the National Academy of Sciences of the United States of America 116 (40): 20097-103. https://doi.org/10.1073/pnas.1912108116.

Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a fatal demyelinating disorder caused by a deficiency in the lysosomal enzyme galactosylceramidase (GALC). GALC deficiency leads to the accumulation of the cytotoxic glycolipid, galactosylsphingosine (psychosine). Complementary evidence suggested that psychosine is synthesized via an anabolic pathway. Here, we show instead that psychosine is generated catabolically through the deacylation of galactosylceramide by acid ceramidase (ACDase). This reaction uncouples GALC deficiency from psychosine accumulation, allowing us to test the long-standing "psychosine hypothesis." We demonstrate that genetic loss of ACDase activity (Farber disease) in the GALC-deficient mouse model of human GLD (twitcher) eliminates psychosine accumulation and cures GLD. These data suggest that ACDase could be a target for substrate reduction therapy (SRT) in Krabbe patients. We show that pharmacological inhibition of ACDase activity with carmofur significantly decreases psychosine accumulation in cells from a Krabbe patient and prolongs the life span of the twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse utilized l-cycloserine, which inhibits an enzyme several steps upstream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding of psychosine synthesis, confirm the long-held psychosine hypothesis, and provide the impetus to discover safe and effective inhibitors of ACDase to treat Krabbe disease.

2018

Deming, Yuetiva, Zeran Li, Bruno A Benitez, and Carlos Cruchaga. (2018) 2018. “Triggering Receptor Expressed on Myeloid Cells 2 (TREM2): A Potential Therapeutic Target for Alzheimer Disease?”. Expert Opinion on Therapeutic Targets 22 (7): 587-98. https://doi.org/10.1080/14728222.2018.1486823.

There are currently no effective therapeutics for Alzheimer disease (AD). Clinical trials targeting amyloid beta thus far have shown very little benefit and only in the earliest stages of disease. These limitations have driven research to identify alternative therapeutic targets, one of the most promising is the triggering receptor expressed on myeloid cells 2 (TREM2). Areas covered: Here, we review the literature to-date and discuss the potentials and pitfalls for targeting TREM2 as a potential therapeutic for AD. We focus on research in animal and cell models for AD and central nervous system injury models which may help in understanding the role of TREM2 in disease. Expert opinion: Studies suggest TREM2 plays a key role in AD pathology; however, results have been conflicting about whether TREM2 is beneficial or harmful. More research is necessary before designing TREM2-targeting therapies. Successful therapeutics will most likely be administered early in disease.

Diez-Fairen, Mónica, Bruno A Benitez, Sara Ortega-Cubero, Oswaldo Lorenzo-Betancor, Carlos Cruchaga, Elena Lorenzo, Lluis Samaranch, et al. (2018) 2018. “Pooled-DNA Target Sequencing of Parkinson Genes Reveals Novel Phenotypic Associations in Spanish Population.”. Neurobiology of Aging 70: 325.e1-325.e5. https://doi.org/10.1016/j.neurobiolaging.2018.05.008.

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

2017

Ibanez, Laura, Umber Dube, John Budde, Kathleen Black, Alexandra Medvedeva, Albert A Davis, Joel S Perlmutter, Bruno A Benitez, and Carlos Cruchaga. (2017) 2017. “TMEM230 in Parkinson’s Disease.”. Neurobiology of Aging 56: 212.e1-212.e3. https://doi.org/10.1016/j.neurobiolaging.2017.03.014.

A study on familial Parkinson disease (PD) described 4 variants in the gene TMEM230 (Chr. 20p13) as the cause of PD. The aim of this study was to test if variants in the TMEM230 gene are associated with PD in 2 independent American European data sets. No variants in the TMEM230 region were found associated with PD, age at onset, or cerebrospinal fluid α-synuclein levels.

Ortega-Rojas, Jenny, Carlos E Arboleda-Bustos, Luis Morales, Bruno A Benitez, Diana Beltrán, Álvaro Izquierdo, Humberto Arboleda, and Rafael Vásquez. (2017) 2017. “[Study of Genetic Variants in the BDNF, COMT, DAT1 and SERT Genes in Colombian Children With Attention Deficit Disorder].”. Revista Colombiana de Psiquiatria 46 (4): 222-28. https://doi.org/10.1016/j.rcp.2016.08.006.

BACKGROUND: Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population.

OBJECTIVES: To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City.

METHODS: We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD.

RESULTS: The TDT analysis showed that no individual allele of any variant studied has a preferential transmission.

CONCLUSIONS: Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population.

Ibanez, Laura, Umber Dube, Benjamin Saef, John Budde, Kathleen Black, Alexandra Medvedeva, Jorge L Del-Aguila, et al. (2017) 2017. “Parkinson Disease Polygenic Risk Score Is Associated With Parkinson Disease Status and Age at Onset But Not With Alpha-Synuclein Cerebrospinal Fluid Levels.”. BMC Neurology 17 (1): 198. https://doi.org/10.1186/s12883-017-0978-z.

BACKGROUND: The genetic architecture of Parkinson's Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1-42, t-tau and p-tau).

METHODS: The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry.

RESULTS: The PRS was associated with PD status (p = 5.83×10-08) and age at onset (p = 5.70×10-07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS.

CONCLUSION: Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.

2016

Davis, Albert A, Kristin M Andruska, Bruno A Benitez, Brad A Racette, Joel S Perlmutter, and Carlos Cruchaga. (2016) 2016. “Variants in GBA, SNCA, and MAPT Influence Parkinson Disease Risk, Age at Onset, and Progression.”. Neurobiology of Aging 37: 209.e1-209.e7. https://doi.org/10.1016/j.neurobiolaging.2015.09.014.

Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.