Research Summary

The goal of our research program is to understand how neuronal diversity is generated in healthy brain and lost in neurological disorders


Back in the 19th century Ramon y Cajal beautifully documented the presence of morphologically diverse types of nerve cells in the nervous system. Since then, neurons have been classified in types and subtypes based on their shape, position, neurotransmitter activity, synaptic target or gene expression profile. The integration of all these parameters ultimately determines the identity and function of each neuronal type and lead to the vast cellular diversity that build up the complex human brain.

Cellular diversity in the brain is achieved during the development by the control of gene expression in response to cell-cell interactions and extracellular cues. However, several stimuli can alter diversity by selectively compromising development, function or survival of specific neurons, both pre- or postnatally. This is best illustrated by neurodegenerative disorders that deal with selective neuronal loss, such as the well-known Parkinson’s disease or Amyotrophic Lateral Sclerosis.

In an effort to understand how genes and genetic regulation control human brain diversity in health and disease, our lab studies mechanisms that perturb specific neuronal type generation, function or survival in neurodevelopmental genetic diseases. These are often caused by mutations in widely expressed genes, and yet, mostly affect specific type of neurons. Following an inside-out approach we first study pathogenic mechanisms caused by particular genetic mutations, and then we uncover common features that provide vulnerability to neuronal types affected by diverse genetic mutations. This approach holds the promise to uncover molecular and functional features of specific neural types and to link them with selective neuronal vulnerabilities to imbalances that occur in neurological diseases. 

Specific projects

Our 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 specific goal of our projects is to uncover particularities of these neuronal types, to better understand disease mechanisms, and to explore treatment options.

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. Using 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 like 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 in our understanding of the regulatory mechanisms that control neuronal subtype function and maintenance in health and disease, and to uncover new routes to treat neurological disorders.

Other questions that excite us


  1. How is the energy molecule balance (i.e. ATP and GTP) regulated in the brain? And how does this affect the human brain function and complexity?
  2. Does protein synthesis regulation cooperate with transcriptional mechanisms for neuronal diversity generation during development?
  3. Is there a neuronal diversification of autophagic regulation?
  4. Can we rationally develop novel therapeutic targets for medulloblastoma?