Carolina Konrdorfer Rangel

I am a PhD student at the Princess Máxima Center (Utrecht) under the supervision of Dr. Willianne Vonk. I graduated in Pharmaceutical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS – Brazil), and recently finished my masters in the program Molecular and Cellular Life Sciences at Utrecht University. My experience in neurosciences started during my bachelor’s, when I had the opportunity to study Huntington’s disease and Spinocerebellar ataxia type 3 while working as an undergraduate intern in a research lab at Hospital de Clinicas de Porto Alegre (HCPA) in Brazil and later at University Medical Center Groningen (UMCG) with Prof. Dr. Harm Kampinga. In these two research groups, I had the chance to study outliers of the correlation between age of onset and CAG length and the co-chaperone DNAJB6, respectively. Afterwards, during my master’s, I worked in the lab of Prof. Dr. Jeroen Pasterkamp at University Medical Center Utrecht (UMCU), where I investigated the relation between Temporal Lobe Epilepsy, miRNA, and snoRNAs. For my master’s final internship, I had the opportunity to work at Prof. Dr. Don Cleveland’s lab at University of California San Diego (UCSD) for 6 months, studying the role of Stathmin-2 in axon regeneration in Amyotrophic Lateral Sclerosis background.

In my PhD project, part of WP4 of the CureQ consortium, I will be focusing on the Tailless complex polypeptide 1 ring complex – TRiC, also known as chaperonin containing tailless complex polypeptide 1 (CCT). This chaperonin is an ATP-dependent hetero-oligomeric complex formed by eight different subunits (CCT1-CCT8), and it is required for the folding of approximately 10-15% of the cellular proteome, including tubulin and actin. In addition to its folding capacity, TRiC/CCT has been shown to be a potent suppressor of aggregation caused by the expression of mutated, polyglutamine-expanded huntingtin (mHTT) in yeast, mouse, and human cells, including striatal-derived neurons. Consequently, the chaperonin protects against cellular toxicity caused by polyglutamine aggregation. Importantly, recent studies indicated that the apical domain of the TRiC subunit 1 (api-CCT1) is already sufficient to accomplish the protective effect, suggesting a promising molecule for further therapy developments. However, during aging and in Huntington’s Disease patients, the expression of TRiC/CCT in the brain is drastically reduced. Therefore, stabilizing or upregulation of TRiC/CCT in HD may be a promising avenue for therapeutic strategies to delay or even revert disease pathology.

In my PhD project, I will aim to gain increased understanding on how TRiC/CCT, particularly CCT1, interacts with different states of aggregation-prone polyglutamine-expanded Huntingtin, including oligomers and fibrils, using (super-resolution) microscopy and biochemical aggregation assays. Furthermore, I will investigate the fate of these mHTT aggregate intermediates in the cell. Complementing, I aim to identify modes to stabilize or upregulate TRiC/CCT expression in HD.