|Education||MS, Pompeu Fabra (Barcelona)|
Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by motor and cognitive dysfunction due to the death of dopamine neurons in the midbrain. The cause for that specific dopamine neuron loss remains elusive and currently no effective disease-modifying treatment exists.
PD was thought to be sporadic until the 1990s, when mutations segregating with the disease began to be identified. Among these, the missense G2019S mutation in the kinase domain of leucine-rich repeat kinase 2 (LRRK2) is the most prevalent in the familial cases of PD. The G2019S mutation augments LRRK2 kinase activity and studies have shown that blocking LRRK2 kinase activity prevents LRRK2 toxicity. Therefore, research conducted to identify toxic kinase substrates is critical to shed light on LRRK2 pathology and ultimately find therapeutic targets for the disease.
Our lab recently showed that LRRK2 phosphorylation of Ribosomal Protein s15 (Rps15) on threonine 136 is toxic in flies and human neuron models, via a mechanism involving an alteration in normal protein synthesis. However, it remains to be investigated whether Rps15 phosphorylation is also a mediator of LRRK2 neurodegeneration in mammals. Thus, my thesis project involves the generation and characterization of a transgenic mouse model overexpressing either wildtype Rps15 or one of its two possible phospho-variants of Threonine 136. Overall, my work intends to expand the mechanistic understanding of the normal cellular functions of LRRK2 and how those are subverted in disease, as well as providing the research field with a novel animal model of G2019S LRRK2-related PD.
Kim JW, Abalde-Atristain L, Jia H, Dawson VL, Dawson TM. Protein translation in Parkinson’s disease. In: Verstreken P, eds. Parkinson’s Disease: Molecular Mechanisms Underlying Pathology. San Diego, CA: Elsevier. In press.
Martin I, Abalde-Atristain L, Kim JW, Dawson TM, Dawson VL. Abberant protein synthesis in G2019S LRRK2 Drosophila Parkinson disease-related phenotypes. Fly (Austin). 2014;8(3):165-9. PMID 25483009.
Smith C, Abalde-Atristain L, He C, Brodsky BR, Braunstein EM, Chaudhari P, Jang YY, Cheng L, Ye Z. Efficient and allele-specific genome editing of disease loci in human iPSCs. Mol Ther. 2015 Mar;23(3):570-7. PMID 25418680.
Smith C, Gore A, Yan W, Abalde-Atristain L, Li Z, He C, Wang Y, Brodsky RA, Zhang K, Cheng L, Ye Z. Whole-genome sequencing analysis reveals high specificity of CRISPR/Cas9 and TALEN-based genome editing in human iPSCs. Cell Stem Cell. 2014 Jul 3;15(1):12-3. PMID 24996165.