# Determining whether metabolic and mitochondrial pathophysiology are a common feature of three distinct genetic models of ASD

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $240,000

## Abstract

In the last twenty years hundreds of potential genetic risk factors for autism have been identified. The
mechanisms by which these genetic loci are linked to autism however are poorly understood, but many clues
are coming from the use of animal models. Fragile X Syndrome (FXS), neurofibromatosis type 1 (NF1), and
deletions in the Neurexin 1 gene (NRX1) are three such prevalent monogenic forms of autism, that are caused
by loss of FMR1, NF1, and NRX1 gene function, respectively. Recent clinical findings suggest that, in addition
to the well known behavioral and cognitive symptoms associated with these diseases, affected individuals also
present with a variety of systemic phenotypes and metabolic abnormalities, likely due to the pleiotropic effects
of the FMR1, NF1, and NRX1 genes. These findings come in hand with recent evidence implicating mitochondrial
dysfunction in the pathogenesis of intellectual disability related syndromes and autism.
 Our prior studies, as well as that of others, have uncovered that Drosophila and mammalian models of
FXS and NF1 have robust cellular signaling cascade defects, including decreased cAMP and increased
insulin/PI3K signaling. The importance of these signaling defects is shown by the fact that our lab and others,
have demonstrated that increasing cAMP levels is sufficient to restore behavior and cognition in Drosophila and
murine models of FXS and NF1. We have also shown that reduction of insulin signaling in the Drosophila model
of FXS ameliorates circadian and memory phenotypes.
 In our proposed studies we explore mitochondrial function in three Drosophila models of monogenetic
forms of autism to determine if mitochondrial defects exist and if so, define commonalities and differences
amongst them. We will also explore the impact that identified signaling pathway defects have on mitochondrial
function in the NF1 and FXS models to determine if mitochondrial activity may be impacted by these signaling
defects and thus contribute to the phenotypes displayed by these models.

## Key facts

- **NIH application ID:** 10373378
- **Project number:** 1R21MH126257-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** THOMAS A JONGENS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $240,000
- **Award type:** 1
- **Project period:** 2021-12-03 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373378

## Citation

> US National Institutes of Health, RePORTER application 10373378, Determining whether metabolic and mitochondrial pathophysiology are a common feature of three distinct genetic models of ASD (1R21MH126257-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10373378. Licensed CC0.

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