[초청강연] Identifying early events in ALS pathogenesis in MATR3 S85C knock-in mice

Identifying early events in ALS pathogenesis in MATR3 S85C knock-in mice

Jeehye Park, PhD


however, no effective treatment is available for these diseases. Insufficient understanding of the
mechanisms underlying these diseases hinders development of effective treatment strategies. The
fundamental questions that remain unclear are (1) Why are certain neurons particularly vulnerable? (2)
How do targeted neurons undergo degeneration? (3) What are the disease-initiating events leading to
degeneration? My lab investigates these questions by exploiting amyotrophic lateral sclerosis (ALS),
characterized by degeneration of motor-controlling neurons. Recently, my lab established a new ALS
mouse model, MATR3 S85C knock-in (KI) mice. A missense mutation S85C is the most frequently
identified ALS-linked mutation in MATR3, which encodes an RNA binding protein involved in RNA
splicing. We found that the KI mice recapitulate key behavioral and neuropathological features of ALS
including motor deficits, neuromuscular junction (NMJ) defects and Purkinje cell loss. We revealed that
the nuclear loss of MATR3 S85C occurs specifically in the motor neurons and Purkinje cells, but not in
neighboring cells. Our findings led us to hypothesize that nuclear loss of MATR3 S85C in large central
neurons leads to aberrant RNA splicing and subsequent expression changes in genes that are required for
NMJ maintenance and neuronal survival. To test our hypothesis, we are currently investigating the
downstream transcriptional and splicing changes when loss of MATR3 S85C starts to occur. We are also
trying to determine how the ALS-linked mutation alters MATR3 function and properties to understand
how MATR3 loss occurs. Our studies will uncover the molecular mechanism by which the S85C
mutation alters MATR3 function to initiate the disease process. Defining the key early events will
facilitate the development of early prevention and intervention strategies for ALS.

Key words: Amyotrophic lateral sclerosis (ALS), neurodegeneration, MATR3, mouse model, molecular
mechanism