Puglielli Lab

The Puglielli Lab research program focuses broadly on molecular mechanisms of neurodevelopment and neurodegeneration. We employ a combination of biochemical, cellular, molecular, and genetic approaches with in vitro, ex vivo and in vivo models. In 2007, our laboratory reported that nascent proteins could undergo Nε-lysine acetylation in the lumen of the endoplasmic reticulum (ER). This discovery resulted in the identification of a previously unknown biochemical machinery that impacts on the biology of the ER.

The ER acetylation machinery regulates two essential functions of the ER: (i) engagement of the secretory pathway (as part of quality control) and (ii) disposal of toxic protein aggregates that form within the secretory pathway (through reticulophagy/ER-phagy). The ER acetylation machinery also maintains intracellular metabolic communication.

AT-1 (also referred to as SLC33A1) is an ER membrane transporter that functions as an antiporter. It transports acetyl-CoA from the cytosol to the ER lumen in exchange for free CoA. Within the ER, acetyl-CoA is used by ATase1 (also referred to as NAT8B) and ATase2 (also referred to as NAT8) to acetylate ER cargo proteins. Free CoA can then exit the ER through AT-1. The acetylation of ER-transiting glycoproteins regulates engagement of the secretory pathway while acetylation of the autophagy protein ATG9A regulates the disposal of toxic protein aggregates through ER-specific autophagy (also referred to as reticulophagy or ER-phagy).

A dysfunctional ER acetylation machinery has now been linked to developmental delay and premature death, autism spectrum disorder and intellectual disability, peripheral forms of neuropathies, segmental progeria and Alzheimer’s disease. Our laboratory has generated mouse models that mimic the above diseases and dissected relevant pathogenic pathways.