Rodrigo Lopez Gonzalez Laboratory

Research

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both fatal neurodegenerative diseases that have no cure. My laboratory aim is to gain insight into the molecular mechanisms of FTD and ALS by using patient-derived induced pluripotent stem cells (iPSC) as a model system. Our examination of neurons derived from carriers of the C9ORF72 expansion, the most common familial form of FTD/ALS, has allowed us to contribute to the discovery of several novel pathogenic phenotypes, including nuclear cytoplasmic transport defects, RNA splicing abnormalities, oxidative stress, and DNA damage.

Currently, we are developing a new research direction by examining the potential role of genome instability, specifically telomere shortening, chromosome abnormalities, and epigenetic regulation, in the pathogenesis of C9ORF72-related FTD/ALS. Another research interest in the lab is to study iPSC-derived brain organoids since they can self-organize, forming a three-dimensional assembly of neurons and glial cells that are able to make functional connections. This will allow us to study interactions between neuronal and glial cells to understand their individual contributions to disease pathogenesis during neurodegeneration.  

Selected Publications

1. Choi SY, Lee JH, Chung AY, Jo Y, Shin JH, Park HC, Kim H, Lopez-Gonzalez R, Ryu JR, Sun W. (2020) Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis Cell Death Dis. 11(10):888.

2. Choi SY, Lopez-Gonzalez R, Krishnan G, Phillips H, Li A, Seeley WW, Yao W-D, Almeida S, and Gao F-B. (2019). C9ORF72-ALS/FTD-Associated Poly(GR) binds to ATP5α and compromises mitochondria function in vivo. Nat Neurosci. 22:851–862.

3. Lopez-Gonzalez R, Yang D, Pribadi M, Kim T, Krishnan G, Choi SY, Lee S, Coppola G, and Gao F-B. (2019). Partial Inhibition of the Overactivated Ku80-Dependent DNA Repair Pathway Rescues Neurodegeneration in C9ORF72-ALS/FTD. Proc. Natl. Acad. Sci. 116:9628–9633.

4. Cheng W, Wang S, Mestre A, Fu C, Makarem A, Xian F, Hayes L, Lopez-Gonzalez R, Drenner K, Jiang J, Cleveland D, Sun S. (2018). C9ORF72 GGGGCC Repeat-Associated Non-AUG Translation is upregulated upon stress through eIF2α phosphorylation. Nat Commun. 9:51.

5. Gao F-B, Almeida S, and Lopez-Gonzalez R. (2017). Dysregulated molecular pathways in amyotrophic lateral sclerosis–frontotemporal dementia spectrum disorder. The EMBO Journal. 36:2931–2950.

6. Yin S, Lopez-Gonzalez R, Kunz R, Gangopadhyay J, Borufka C, Gygi S, Gao F-B, and Reed R. (2017). Evidence that C9ORF72 dipeptide repeat proteins associate with U2 snRNP to cause mis-splicing in ALS/FTD patients. Cell Reports. 19:2244– 2256.

7. Lopez-Gonzalez R, Lu Y, Gendron TF, Karydas A, Tran H, Yang D, Petrucelli L, Miller BL, Almeida S, and Gao F-B. (2016). Poly(GR) in C9ORF72-related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron. 92:383–391.

8. Biswas MHU, Almeida S, Lopez-Gonzalez R, Mao W, Zhang Z, Karydas A, Geschwind MD, Biernat J, Mandelkow E-M, Futai K, Miller BL, and Gao F-B. (2016). MMP-9 and MMP-2 Contribute to Neuronal Cell Death in iPSC Models of Frontotemporal Dementia with MAPT Mutations. Stem Cell Reports. 7:316–324.

9. Woehlbier U, Colombo A, Saaranen MJ, Pérez V, Ojeda J, Bustos FJ, Andreu CI, Torres M, Valenzuela V, Medinas DB, Rozas P, Vidal RL, Lopez-Gonzalez R, Salameh J, Fernandez-Collemann S, Muñoz N, Matus S, Armisen R, Sagredo A, Palma K, Irrazabal T, Almeida S, Gonzalez-Perez P, Campero M, Gao FB, Henny P, van Zundert B, Ruddock LW, Concha ML, Henriquez JP, Brown RH,* and Hetz C. *(2016). ALS-linked protein disulfide isomerase variants cause motor dysfunction. The EMBO Journal. 8:845-65 (* co-corresponding author).

10. Freibaum BD*, Lu Y*, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. (2015). GGGGCC repeat expansion in C9ORF72 compromises nucleocytoplasmic transport. Nature. 525:129–133. (*: co-first author).

11. Escobedo-Avila I, Vargas-Romero F, Molina-Hernández A, López-González R, Cortés D, De Carlos JA, and Velasco I. (2014). Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors. Mol Brain. 12:7:58.

12. López-González R and Velasco I. (2012). Therapeutic potential of motor neurons differentiated from embryonic stem cells and induced pluripotent stem cells. Archives of Medical Research. 43:1–10.

13. Lopez-Gonzalez R, Camacho-Arroyo I, and Velasco I. (2011). Progesterone and 17 β-estradiol increase differentiation of mouse embryonic stem cells to motor neurons. IUBMB Life. 63:930–939.

14. López-González R, Kunckles P, and Velasco I. (2009). Transient recovery in a rat Model of familial amyotrophic lateral sclerosis after transplantation of motor neurons derived from mouse embryonic stem cells. Cell Transplantation. 18:1171–1181.