Welcome to the Representation Matters Speaker Series hosted by SEAS!

ER Acetylation: the quality control checkmark implicated in neurological disorders and aging

In order for a synapse to occur in the brain, many specialized proteins are required at the synaptic cleft of a neuron. The secretory pathway regulates the synthesis and secretion of these proteins into the membrane and extracellular space. As newly folded polypeptides transit the secretory pathway, the Endoplasmic Reticulum (ER) acetylation machinery ensures two essential functions: selection of properly folded proteins and disposal of unfolded or misfolded proteins. Nε-lysine acetylation has emerged as a central mechanism to maintain quality control and protein homeostasis in the ER. Specifically lysine acetylation in the ER requires 1) a donor of the acetyl group, acetyl-CoA, 2) an acceptor of the acetyl group, a lysine residue on a polypeptide, and 3) an acetyltransferase to transfer the acetyl group from acetyl-CoA to the lysine side-chain. Acetyl-CoA is not synthesized in the ER and therefore it must be transported from the cytosol to the ER lumen by the ER membrane transporter, AT-1.

The essential functions of the ER acetylation machinery not only ensure proper cellular health and function, but also impact the health of the whole organism. A homozygous point mutation in AT-1 results in developmental delay and childhood death, whereas a heterozygous mutation results in a familial form of spastic paraplegia. Gene duplication events in AT-1 have been identified in individuals with autism spectrum disorder, intellectual disability, and dysmorphic features that are consistent with a diagnosis of segmental progeria. Increased dosage and mRNA levels of AT-1 have been detected in late onset Alzheimer’s Disease, and AT-1 increases as a function of age.

In my thesis, we explored the ramifications both upstream and downstream of dysregulated acetyl-CoA flux. We found that AT-1 plays a central role in proper cellular functioning and homeostasis. AT-1 is essential to maintain proper engagement of the secretory pathway and serves as a metabolic regulator by promoting acetyl-CoA homeostasis and intracellular crosstalk.

View the recording of Dr. Dieterich’s presentation here! (Oxy credentials are required)

Best,

The CATALYST x BEARs Team