Research Overview


 

Big Questions

Major Challenges in mechanistic studies on neurodegeneration.

Neurodegenerative diseases are a leading cause of death worldwide. Characterized by a gradual loss of the integrity and function of the nervous system, these diseases are age-related, fatal, increasingly prevalent, and currently incurable. A major challenge to the therapeutic development of these diseases is an incomplete understanding of their pathogenic mechanisms. As the disease onset usually occurs very lately during pathogenesis, many cellular defects, including protein aggregation, mitochondrial dysfunctions, DNA damage, axonal transport abnormalities, etc., are observed in the nerves of patients at the onset. Thus, it is unclear:

  • Which defect(s) is/are the primary cause?

  • How do these defects interconnect to drive pathogenesis?

To address these questions, we need to better understand how cells are organized and how they respond to genetic and environmental stress. Indeed, cellular stress responses play a critical role in aging and age-related diseases, including neurodegenerative diseases. Upon exposure to stress, cells/neurons acutely alter their physiological state to maintain homeostasis. However, chronic stress responses such as those that occur with aging may make these adaptive changes detrimental, thereby contributing to neurodegeneration.

With an overarching goal to treat neurodegenerative diseases, research in the Zhang lab seeks to address two big questions:

  • A disease-related question: What is the molecular mechanism underlying neurodegeneration?

  • A basic-biology-related question: How different cellular organelles/processes functionally connect?

 

C9ORF72-mediated ALS and FTD (c9ALS/FTD)

Research in the Zhang lab mainly focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two fatal neurodegenerative diseases. ALS is a motor neuron disease characterized by muscle weakness and atrophy, whereas FTD is the second most common form of dementia for people under age of 65, characterized by a progressive decline of behavior, movement, and language. Despite the symptomatic differences, increasing evidence suggests that ALS and FTD share clinical, neuropathological, and genetic features and are part of a common spectrum. Indeed, these two diseases 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% ALS cases. Furthermore, several genes have been identified, of which the mutations can cause both ALS and FTD, including the chromosome 9 open reading frame 72 (C9ORF72) gene.

A GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of familial ALS (50%) and FTD (25%) and also presents in some sporadic ALS (8%) and FTD (5%) cases. The lengths of G4C2 HRE in patients are greater than 30 but vary among individuals, with some patients carrying >1,000 repeats. Like many ALS and FTD cases, c9ALS/FTD patients exhibit TDP-43 pathology. However, two unique pathological hallmarks of c9ALS/FTD are foci of repeat RNAs and dipeptide repeat proteins (DPRs), abnormal RNA and protein products of HRE-containing transcripts, respectively. In the past years, researchers have made significant progress in understanding how repeat RNAs and DPRs cause neurodegeneration. Particularly, we and others have identified that repeat RNAs and DPRs cause nucleocytoplasmic transport disruption and stress granule assembly, two critical pathogenic players in c9ALS/FTD.