# Spastic paraplegia, neurodegeneration and autism: possible role for AT- 1/SLC33A1?

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $441,315

## Abstract

We discovered that Nε-lysine acetylation occurs in the lumen of the endoplasmic reticulum (ER) in 2007.
From that initial finding, we went on to discover the entire ER acetylation machinery (one membrane
transporter, AT-1/SLC33A1, and two acetyltranferases, ATase1 and ATase2) and uncover a novel piece of
ER biology. Specifically, we discovered that the ER acetylation machinery regulates proteostasis within the ER
and secretory pathway by maintaining the balance between quality control/engagement of the secretory
pathway and reticulophagy. By using a combination of biochemistry and high-definition mass spectrometry, we
discovered that SLC25A1 and SLC13A5 act as important “metabolic partners” of AT-1.
 Homozygous mutations in AT-1/SLC33A1, SLC25A1 or SLC13A5 are associated with developmental delay
of the brain and early forms of encephalopathy while heterozygous mutations are associated with similar forms
of hereditary sensory and autonomic neuropathies (HSANs), including specific forms of spastic paraplegias.
Important, these mutations either introduce a premature STOP codon or cause loss-of-function of the
transporters. Furthermore, gene duplication events of AT-1/SLC33A1, SLC25A1 or SLC13A5 are associated
with autism spectrum disorder (ASD), intellectual disability, and progeria-like dysmorphism. To expand our
studies, we generated neuron-specific (AT-1 nTg, SLC25A1 nTg, and SLC13A5 nTg) and systemic (AT-1 sTg,
SLC25A1 sTg, and SLC13A5 sTg) overexpressing mice. These animals display important phenotypic
similarities, supporting the conclusion that we have identified a unified metabolic pathway that is at the basis of
closely related neurodegenerative and neurodevelopmental diseases across lifespan. To complement the
above studies and dissect the specific role of the two ATases, down-stream of AT-1, we have also generated
Atase1-/- and Atase2-/- mice. Their phenotype supports the idea that these two ER-based acetyltransferases
have evolved to play partially divergent roles. The GENERAL HYPOTHESIS of this research is that SLC25A1,
SLC13A5, and AT-1 act in concert to regulate engagement of the secretory pathway and induction of
reticulophagy. Specific Aim 1 will test the hypothesis that the ER acetylation machinery is the downstream
target of a dysfunctional cytosol-to-ER flux of acetyl-CoA caused by the duplication of AT-1, SLC25A1 or
SLC13A5. Specific Aim 2 will use our newly generated Atase1-/- and Atase2-/- mice to test the hypothesis that
ATase1 and ATase2 have partially different biological functions. Specific Aim 3 will test the hypothesis that
specific structural features of newly identified AT-1 downstream targets allow fine tuning of reticulophagy. In
conclusion, this proposal is the result of novel discoveries made in our laboratory; it will help us dissect the
molecular mechanisms of severe neurodegenerative and neurodevelopmental diseases across lifespan and it
will allow us dissect essential molecular and biochemical functions of the ...

## Key facts

- **NIH application ID:** 10116004
- **Project number:** 2R01NS094154-06
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Luigi Puglielli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,315
- **Award type:** 2
- **Project period:** 2015-09-20 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116004

## Citation

> US National Institutes of Health, RePORTER application 10116004, Spastic paraplegia, neurodegeneration and autism: possible role for AT- 1/SLC33A1? (2R01NS094154-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10116004. Licensed CC0.

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