The exponential increase of genetic studies over the last few decades has uncovered numerous genetic variants associated to neurological disorders. Often, these variants are widely expressed in every tissue and yet they exclusively disrupt the development, function, or viability of specific neural populations. In fact, specific neuronal vulnerability is surprisingly common in many neurological diseases. But why are some neurons vulnerable to disease stimuli and why are others resistant? What determines the response of each neural type to diverse physiological and pathological conditions? And how does each neural type acquire and maintain specialized functions? These are the central questions that guide research in the Akizu Lab, which works toward a better understanding of human brain complexity in health and disease.
In an effort to understand how genes and genetic regulation control human brain diversity in health and disease, the lab studies mechanisms that perturb specific neuronal type generation, function, or survival in genetically inherited pediatric neurodegenerative diseases. The lab’s current focus centers on childhood neurodegenerative disorders of the cerebellum and motoneurons associated to perturbed protein synthesis and degradation events. These are often caused by mutations in widely expressed genes and yet mostly affect specific types of neurons.
Following an inside-out approach, the Akizu Lab first studies pathogenic mechanisms caused by particular genetic mutations, and then the research team works to uncover common features that provide vulnerability to neuronal types affected by diverse genetic mutations. The team combines mouse models and human stem cell-derived cultures, and apply DNA/RNA sequencing, proteomics, metabolomics and imaging methods to gain insights into functional and molecular differences between resistant and vulnerable cells. This approach holds the promise of uncovering molecular and functional features of specific neural types and novel therapeutic opportunities for neurological disorders that the lab studies.
- How do deficiencies in protein synthesis pathways lead to cell type specific vulnerabilities? Using pluripotent stem cells and murine models, the Akizu Lab studies how AMPD2 deficiency leads to protein synthesis collapse.
- Why is cerebellar tissue vulnerable to lysosomal dysfunction? The lab is studying how SNX14 dependent defects on lysosomal and autophagic pathways lead to selective cerebellar atrophy and intellectual disability.
- What are the protein homeostasis regulatory mechanisms involved in selective neuronal vulnerability? The goal of this project is to identify cell type specific protein homeostasis pathways involved in selective neuronal vulnerability.