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.
News
Taking out the trash: New study finds clearing specific cell “trash” is possible and may be target for future treatments of neurodegenerative diseases
Cells make a lot of trash. Probably more than you’d think. So, cells have a trash disposal system that efficiently cleans up and recycles any waste that is produced. But when there are issues with …
Malfunctioning quality control pathway in neurons may be a cause of autism spectrum disorder
While researchers believe there is no single cause for Autism Spectrum Disorder (ASD), two new studies by Luigi Puglielli, MD, PhD, reveal a new potential genetic connection as a cause of the condition. As our …
The identities of enzymes: study further defines the function of a potential target for Alzheimer’s therapy
A new study from the lab of UW-Madison professor of medicine Luigi Puglielli, MD, PhD, opens a door to potential treatments for diseases of age, such as Alzheimer’s disease, by defining the roles of two …
- Read more news