Pedro Fernandez-Funez, PhD
Associate Professor, Medical School, Duluth Campus
Associate Professor, Medical School, Duluth Campus
Post-Doctoral, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX
Ph.D., Developmental Biology and Genetics, Universidad Autonoma de Madrid (Spain)
B.S., Universidad Autonoma de Madrid (Spain)
Statement: My aim is to unravel the molecular mechanisms underlying neurodegeneration using Drosophila models of several proteinopathies.
A large group of human neurodegenerative conditions are associated to protein deposition in the brain. Some of the most common brain conditions include Alzheimer’s, Parkinson’s, and Huntington’s disease, all of which are devastating and incurable. Prion disorders are rare and transmissible, but belong to the same class of neurodegenerative diseases. The common feature of these and many other diseases is the deposition of misfolded proteins in brain neurons proposed to be responsible for neuronal cell death. The proteins responsible for each disease (Amyloid-beta in AD, alpha-Synuclein in PD, Huntingtin in HD and the Prion protein in PrD) are quite different in sequence, function and cellular localization. However, they are all structurally unstable and prone to misfold, thus exposing hydrophobic pockets that make the proteins aggregate. Upon autopsy, these proteins accumulate in large, fibrillar aggregates that were originally thought to be responsible for neurodegeneration. However, the focus has recently turned to smaller, soluble aggregates (oligomers) that are highly toxic and seem capable of disrupting synaptic function. This knowledge, though, has not resulted in significant insight into the causes of neuronal cell death nor has produced effective therapies.
I am using the flexibility and genetic prowess of Drosophila to gain knowledge on some of the most intractable questions posed by this group of neurodegenerative diseases. Recent work includes the identification of engineered antibodies and chaperones that bind amyloid-beta and efficiently suppress its toxicity. I also generated a robust phenotypic Drosophila model expressing the prion protein in the eye that I will use to conduct genetic screens to identify genetic modifiers of PrP neurotoxicity. I am also interested in uncovering the pathogenic mechanisms mediating the toxicity of several genes implicated in amyotrophic lateral sclerosis (ALS).
My lab uses the power of genetics to do discoveries and we also utilize neuroscience, cell biology, molecular biology, protein biochemistry, imaging, histology, and behavioral techniques to conduct comprehensive studies on relevant genes implicated in neurodegeneration.
See full list of publications at: PubMed
1. Fernandez-Funez P, Lu C-H, Rincon-Limas DE, Garcia-Bellido A and Botas J (1998). The relative expression amounts of apterous and its co-factor dLdb/Chip are critical for dorso-ventral compartmentalization in the Drosophila wing. EMBO J. 17: 6846-6853. PMID: 9843490
2. Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She W-C, Luchak JM, Martinez P, Turiegano E, Benito J, Capovilla M, Skinner PJ, McCall A, Canal I, Orr H, Zoghbi HY and Botas J (2000). Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408: 101-106 (Featured in Nat Rev Neurosci. (2000) 1:154), PMID: 11081516
3. Chen H-K, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EMC, Orr H, Botas J and Zoghbi HY (2003). Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 457-468. (Cover image, Featured in Science, 301: 59-60). PMID: 12757707
4. Martin-Peña A, Acebes A, Rodriguez JR, Sorribes A, de Polavieja GG, Fernandez-Funez P* and Ferrus A (2006). Age-independent synaptogenesis by phosphoinositide 3 kinase. J. Neuroscience 26: 10199-10208. PMID: 17021175
5. Branco J, Al-Ramahi I, Ukani L, Perez AM, Fernandez-Funez P, Rincon-Limas D and Botas J (2008). Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Human and Molecular Genetics 17: 376-390. PMID: 17984172
6. Casas-Tinto S, Gomez-Velazquez M, Granadino B and Fernandez-Funez P* (2008). FoxK mediates TGF-beta signalling during midgut differentiation. J. Cell Biol. 183: 1049-1060. PMCID: 2600746
7. Fernandez-Funez P*, Casas-Tinto S, Zhang Y, Gomez-Velazquez M, Morales-Garza, MA, Cepeda-Nieto AC, Castilla J, Soto C and Rincon-Limas DE (2009). In Vivo Generation of Neurotoxic Prion Protein Isoforms: Role for Hsp70 in Prion Protein Conversion. PLoS Genetics 5: e1000507. PMID: 19503596
8. Fernandez-Funez P*, Casas-Tinto S and Rincon-Limas DE (2010). Exploring prion protein biology in flies: genetics and beyond. Prion 4: 1-8. PMID: 20083902.
9. Fernandez-Funez P*, Zhang Y, Casas-Tinto S, Xiao X, Zou WQ, Rincon-Limas DE (2010). Sequence-dependent prion protein misfolding and neurotoxicity. J. Biol. Chem. 285: 36897-908. PMID: 20817727.
10. Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE Fernandez-Funez P* (2011). The ER-stress transcription factor XBP1s prevents Amyloid-ß neurotoxicity. Human and Molecular Genetics 20: 2144-60. PMID: 21389082.
11. Zou W-Q, Xiao X, YuanJ, Fujioka H, Wang X, Richardson S, Zhou X, Zou R, Li S, Zhu X, McGeer PL, McGeehan J, Kneale G, Rincon-Limas DE, Fernandez-Funez P, Lee H, Petersen RB, Smith MA, and Guo JP (2011). Amyloid-?42 interacts mainly with insoluble prion protein in the Alzheimer’s brain. J. Biol. Chem. 286: 15095-105. PMID: 21393248
12. Tare M, Modi RM, Nainaparampil JN, Bedi S, Fernandez-Funez P, Kango-Singh M and Singh A (2011). Activation of JNK signaling mediates Amyloid-ß-dependent cell death. PLoS One 6: e24361, PMID: 21949710
13. Fernandez-Funez P*, Zhang Y, Casas-Tinto S, Jensen K, Zou WQ, Rincon-Limas DE (2011). Pulling rabbits to reveal the secrets of the prion protein. Comm. and Integra. Biol. 4: 262-266. PMID: 21980555
14. Castillo-Carranza DL, Zhang Y, Guerrero-Muñoz MJ, Kayed R, Rincon-Limas DE and Fernandez-Funez P* (2012). Differential activation of the ER stress factor XBP1 by oligomeric assemblies. Neurochem. Res. 37: 1707-17. PMID: 22528838.
15. Rincon-Limas DE, Jensen K and Fernandez-Funez P* (2012). Drosophila models of proteinopathies: the little fly that could. Curr. Pharm. Design 18: 1108-22. PMID: 22288402
16. Jensen K, Williams C, Sanchez-Garcia J, Khare S, Mathur K, Graze RM, Hahn DA, McIntyre LM, Rincon-Limas DE and Fernandez-Funez P* (2013). Purification of transcripts and metabolites from Drosophila heads. Journal of Visualized Experiments 73: doi: 10.3791/50245. PMID: 23524378
17. Fernandez-Funez P*, Malaga-Trillo E and, Rincon-Limas DE (2013) Alternative models of prion diseases. In: Zou WQ and Gambetti P (eds) Prions and prion diseases, 1st edn. Springer, New York.
18. Fernandez-Funez P*, Sanchez-Garcia J and Rincon-Limas DE (2013). Contribution of the Drosophila eye to unraveling the basis of neurodegeneration in: Singh A (ed) Molecular genetics of axial patterning, growth and disease in Drosophila eye, 1st edn. Springer, New York.
19. Zhang Y, Arcia S, Perez B, Fernandez-Funez P* and Rincon-Limas DE (2013). p?TubHA4C, a new versatile vector for constitutive expression in Drosophila. Molecular Biology Reports 40: 5407-15. PMID: 23681549.
20. Sanchez-Garcia J, Arbelaez D, Jensen K, Rincon-Limas DE and Fernandez-Funez P* (2013). Polar substitutions in helix 3 produce toxic, transmembrane isoforms of the Prion protein. Human and Molecular Genetics 22: 4253-4266. PMID: 23771030.
21. Zhang Y, Casas-Tinto C, Rincon-Limas DE and Fernandez-Funez P* (2014). Combined pharmacological induction of Hsp70 suppresses prion protein neurotoxicity in Drosophila. PLoS One 9: e88522. PMID: 24523910
22. Fernandez-Funez P and Rincon-Limas DE. (2014). Activating Hsp70 neuroprotection: two drugs better than one. Editorial for Cell Cycle 13, 1657-8. PMID: 24810400
23. Gallego-Iradi C, Bickford JS, Khare S, Hall A, Nick JA, Salmasinia D, Wawrowsky K, Bannykh S, Huynh, DP, Rincon-Limas DE, Pulst SM, Nick HS, Fernandez-Funez P and Waters MF (2014). KCNC3R420H, a K+ channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. Neurobiology of Disease 71: 270-79. PMID: 25152487
24. Choong HL, Blackband SJ and Fernandez-Funez P* (2015). Visualization of synaptic domains in the Drosophila brain by magnetic resonance microscopy at 10 micron isotropic resolution. Scientific Reports 5: 8920. DOI: 10.1038/srep08920. PMID: 25753480
25. de Mena Alvarez L, Fernandez-Funez P, Sanchez-Garcia J and Rincon-Limas DE (2015). Protein misfolding in brain aging and neurodegenerative diseases. In: Vaiserman A, Moskalev A and Pasyukova E (eds) Life Extension: Lessons from Drosophila, 1st edn. Springer, New York.
26. Fernandez-Funez P*, de Mena L and Rincon-Limas DE (2015). Modeling the complex pathology of Alzheimer’s disease in Drosophila. Experimental Neurology 274: 58-71. PMID: 26024860
27. Fernandez-Funez P*, Zhang Y, Sanchez-Garcia J, Khare S, Golde T, Levites Y and Rincon-Limas DE (2015). Single chain variable fragment antibodies exert distinct and synergistic neuroprotective activities in Drosophila models of Alzheimer’s disease. Human and Molecular Genetics 24: 6093-105. PMID: 26253732
28. Fernandez-Funez P*, Sanchez-Garcia J, Zhang Y, Khare S, Levites Y, Golde T and Rincon-Limas DE (2016). Engineered extracellular Hsp70 suppresses Amyloid-ß neurotoxicity in Drosophila. PNAS, 113(35): E5212-21. doi: 10.1073/pnas.1608045113. PMID: 27531960
29. Sanchez-Garcia J, Jensen K, Zhang Y, Rincon-Limas DE and Fernandez-Funez P* (2016). A protective amino acid from dog prion protein suppresses the toxicity of mouse prion protein. Neurobiol. Dis. 95:204-9. doi: 10.1016/j.nbd.2016.07.025. PMID: 27477054
30. Fernandez-Funez P, Sanchez-Garcia J, Rincon-Limas DE. Drosophila models of prionopathies: insight into prion protein function, transmission, and neurotoxicity. Curr Opin Genet Dev. 2017 Jun;44:141-148. doi: 10.1016/j.gde.2017.03.013. Epub 2017 Apr 14. Review. PMID: 28415023
31. de Mena L, Chhangani D, Fernandez-Funez P & Rincon-Limas DE. secHsp70 as a tool to approach amyloid-?42 and other extracellular amyloids. Invite short communication to FLY. Fly (Austin). 2017 Jul 3;11(3):179-184. doi: 10.1080/19336934.2017.1291104. Epub 2017 Feb 6. PMID: 28165856
32. Martin-Peña JA, Rincon-Limas DE and Fernandez-Funez P*. Anti-A? single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer's disease. e. Sci Rep. 2017 Sep 12;7(1):11268. doi: 10.1038/s41598-017-11594-2 PMID: 28900185
33. Khare S, Nick JA, Butler B, Khoshbouei H, Hathorn T, Ranum LPW, Smithson L, Golde TE, Paucar M, Morse R, Raff M, Simon J, Nordenskjöld M, Wirdefeldt K, Rincon-Limas DE, Lewis J, Fernandez-Funez P, Nick HS, Waters MF. A KCNC3 mutation causes a neurodevelopmental, non-progressive form of SCA13 displaying neuroplasticity and an association with abnormal EGFR trafficking. PLoS One. 2017 May 3;12(5):e0173565. doi: 10.1371/journal.pone.0173565. eCollection 2017. PMID: 28467418
- Brain pathologies and genetics of brain disorders
- Course Director: NeuroMedicine
- Facilitator: Problem based learning (PBL) in NMED, IHO, CRAAB I and II
Mentoring/Advising: undergraduates, post-doctoral fellows.