I. ALS and FTD

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease sometimes associated with frontotemporal dementia (FTD), the most common type of dementia for people under the age of 45. ALS is characterized by muscle weakness and atrophy, whereas FTD is characterized by frontotemporal lobe degeneration. Despite their symptomatic differences, ALS and FTD share clinical, pathological, and genetic features and are part of a common spectrum. They can occur in the same family, and many ALS or FTD patients develop signs of the other disease. In addition, the most common pathological subtype of FTD (~50%) is characterized by TDP-43 deposition, a pathological hallmark observed in ~98% of ALS cases. Furthermore, several genes have been identified whose mutations can cause both FTD and ALS, including chromosome 9, open reading frame 72 (C9ORF72).

1. Stress Granule

Upon stress, cells halt their translation and assemble large mRNA/RNA-binding protein condensates called "stress granules." The assembly of these granules is mediated by the condensation of RNAs and proteins, a process that can cause some of these proteins, including TDP-43, FUS, etc., to aggregate. As the aggregation of these proteins is a pathological hallmark of ALS and FTD, stress granules are believed to play a critical role in pathogenesis. Indeed, inhibiting stress granule assembly suppresses neurodegeneration in multiple models of ALS/FTD, supporting the pathogenic role of stress granules. Using animal and cellular models, we seek to understand how stress granules are regulated, how they cause cytotoxicity, and how they are implicated in ALS and FTD.

Related Publications

1. 1) Sahana et al., (2023) c-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD. Journal of Neuroscience. 43(17):3186-3197.
   

2. 2) Gao, et al., (2022) Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins. Science Translational Medicine. 14(662):eabq3215.

3. 3) Zhang, et al., (2018) Stress granule assembly disrupts nucleocytoplasmic transport. Cell. 173(4):958-971.e17.

2. Pathomechanism Based on Multiomic Analyses

Biomedical research has entered the Big Data era. Patient multi-omic analyses have generated many data, which could provide important indications of human diseases. However, a major challenge is to extract meaningful information from these data and use them to guide our studies to elucidate pathomechanisms, identify biomarkers, and develop therapeutics. To this end, we collaborate with computer biologists and bioinformaticians and use our animal and cellular models to study pathomechanism.

Related Publication

Pun et al., (2022) Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform. Front. Aging Neurosci.

II. Hereditary Neurodevelopmental Disorders

There are 20,000 genes in the human genome. However, less than 20% of them have their functions characterized, with the vast majority having their functions unknown. However, many of these genes are essential to the nervous system, and their mutations can cause neurological problems in humans. These diseases are considered "rare" because they each affect a very small portion of the population, but together they are not "rare" because there are more than 2,000 types of them. Furthermore, these mendalian diseases usually affect neurodevelopment and are incurable, preventing the patients from reaching puberty, thereby creating an unignorable challenge to families and society. Using animal and cellular models, we seek to understand how these diseases affect the nervous system and identify therapeutic targets.

1. Leigh Syndrome and Other Mitochondrial Encephalopathy

Mitochondria play a key role in many cellular processes, such as ATP synthesis, metabolism, and signaling transduction, and their defects can cause many types of neurodevelopmental disorders. A typical mitochondrial disorder is Leigh syndrome, a.k.a., infantile subacute necrotizing encephalomyelopathy, a clinically and genetically heterogeneous neurodevelopmental and degenerative disorder caused by energy deficiency.  It is also the most common infantile neurological disorder in China. In addition, many other mitochondrial disorders may also present with Leigh-like symptoms. Using Drosophila and mice as models, previous studies have identified important roles of lipid droplets and glia in Leigh syndrome pathogenesis. Collaborating with Shenzhen Children's Hospital, we are currently relating mitochondrial defects to other cellular and molecular defects in the nervous system to better understand disease pathomechanism and identify potential therapeutic targets.

Related Publications

1) Liu et al., (2015) Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration. Cell. 160(1-2):177-90.

2) Zhang et al., (2013) The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. J Cell Biol. 200(6):807-20.

2. Microcephaly

Microcephaly is a rare but very challenging medical condition. Characterized by a smaller-than-regular head size, it is observed in many neurodevelopmental disorders, usually accompanied by intellectual disability, developmental delay, seizures, ataxia, etc. Mutations in many genes can cause microcephaly, but its underlying mechanism is unclear. Previous studies suggested an important role of neural stem cells--defects in their activation, proliferation, or differentiation may cause microcephaly. However, what regulates these processes is unclear. Collaborating with Shenzhen Children's Hospital, we seek to discover novel genes regulating neural stem cells and identify their roles in microcephaly. We also perform drug screens to identify potential therapeutics.

Appendix: How we study a project

1.   Find an important question—neurological diseases.

2.  Genetics never lies, although it doesn't tell you the mechanism.

3.  Begin with an unbiased approach, e.g., a genome-wide screen.

4.  Dissect the mechanism, which is usually not easy.

a)  Unbiased, unbiased, unbiased.

b)  Always follow positive data.

c)  Move forward step-by-step, do not jump.

d)  Sometimes, we need a hypothesis—test it.

e)  If the hypothesis is wrong, step back. Come up with another one.

5.  Summarize the data, and write manuscripts.