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Akizu Lab Research Overview
The Akizu Lab's current research is focused on uncovering functional and molecular features of cerebellar and motor neurons. These neuronal populations are particularly vulnerable to ubiquitous stimuli that alter protein synthesis and degradation, and lead to perinatal neurodegenerative disorders such as cerebellar ataxias and spastic paraplegias.
The lab studies neurodevelopmental and childhood neurodegenerative disorders caused by genetic and epigenetic alterations. We combine mouse models and human stem cell-derived cultures, and apply CRISPR genome editing, DNA/RNA sequencing, proteomics, metabolomics and imaging methods to gain insights into functional and molecular differences between resistant and vulnerable neurons.
Our projects aim to uncover particularities of these neuronal types, to better understand disease mechanisms, and to explore treatment options with the ultimate goal of leveraging the information we gather from these studies to develop therapeutic strategies.
Being essential and ubiquitous cellular pathways, how do deficiencies in protein synthesis pathways lead to diverse cell type vulnerabilities?
Adenosine Monophosphate Deaminase 2 (AMPD2) deficiency is a novel purine nucleotide metabolism disorder that, depending on the affected AMPD2 isoform, causes a perinatal neurodegeneration typically seen in Pontocerebellar Hypoplasias (PCH) or corticospinal motoneuron degeneration characteristic of Hereditary Spastic Paraplegia (HSP). AMPD2 is widely expressed across all the tissues and implicated in protein synthesis regulation. Using in vitro differentiation of pluripotent stem cells and murine models, we are studying why neurons are more vulnerable than other cells in the body to metabolic derangement and protein synthesis collapse caused by AMPD2 deficiency.
The success of this experimental approach will also set the stage to uncover a potential link between diversity in global and local protein synthesis regulation and selective neuronal vulnerability.
Why is cerebellar tissue exquisitely sensitive to lysosomal dysfunction?
Sorting nexin 14 (SNX14) is a poorly characterized member of Sorting Nexin family of proteins. We recently found that SNX14 acts on late endosome-lysosome compartments and interferes with autophagic clearance. SNX14 loss-of-function mutations lead to a syndromic form of cerebellar ataxia with intellectual disability. Working with a mouse model that we have generated with CRISPR technology, as well as cerebellar organoids generated from human pluripotent stem cells, we are studying how SNX14 dependent defects on lysosomal and autophagic pathways lead to selective cerebellar atrophy and intellectual disability.
This project has the potential to uncover therapeutic targets to treat other type of cerebellar ataxias, which are frequently linked to lysosomal and autophagic dysfunction.
In addition, this project may reveal novel neuronal networks and molecular pathways involved in the pathogenesis of intellectual disability.
What are protein homeostasis regulatory mechanisms involved in selective neuronal vulnerability?
In addition to AMPD2 and SNX14 deficiency, disruption of protein synthesis and degradation are found in common neurological disorders including neurodevelopmental disorders such as autism spectrum disorders, as well as neurodegenerative disorders such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis. We are working to test the hypothesis that neural type specific diversity in protein homeostasis regulation contributes to selective neuronal vulnerability. To achieve this goal, we are implementing genetic functional screenings in mouse brain and neural cultures followed by imaging, DNA/RNA sequencing, and mass spectrometry techniques.
Together, these results will advance our understanding of the regulatory mechanisms that control neuronal subtype function and maintenance in health and disease, and uncover new routes to treat neurological disorders.