Cerebellar synaptic vulnerability in friedreich ataxia glur2 palmitoylation deficits in purkinje cells Elizabeth Mercado Ayon

Format:

Book

Thesis/Dissertation

Author/Creator:

Mercado Ayon, Elizabeth, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Cellular biology.

Molecular biology.

0317.

0379.

0307.

Local Subjects:

Neurosciences.

Cellular biology.

Molecular biology.

0317.

0379.

0307.

Genre:

Academic theses

Physical Description:

1 online resource (132 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Friedreich's ataxia (FRDA) is an autosomal recessive multisystemic disorder caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster biogenesis. Frataxin deficiency disrupts mitochondrial function, impairing key metabolic pathways including glucose and fatty acid oxidation. Although this metabolic dysfunction affects multiple organ systems, neurological deficits-particularly those involving the cerebellum-remain the ubiquitous clinical feature. Despite well-characterized neuropathology, including degeneration of dentate nucleus neurons and disruption of cerebellar circuitry, the molecular mechanisms linking frataxin deficiency to cerebellar neuronal and synaptic vulnerability remain incompletely understood. This dissertation investigates the impact of frataxin deficiency on cerebellar structure and synaptic integrity with a focus on Purkinje cells, using complementary mouse models of FRDA, including the doxycycline-inducible frataxin knockdown (FRDAkd) and the Knock-in/Knockout (KIKO) models. Across models, frataxin deficiency is associated with early alterations in synaptic components, including reductions in AMPA receptor subunits, particularly GluR2, and dysregulation of glutamate transporters. These changes occur before an overt behavioral phenotype, in association with largely preserved Purkinje cell number and morphology at early stages of frataxin deficiency, suggesting that synaptic alterations precede overt neurodegeneration. Mechanistic studies indicate that reduced GluR2 protein levels are independent of mRNA expression or Purkinje cell number but instead reflect impaired post-translational modification. Specifically, GluR2 palmitoylation is selectively and significantly reduced in the FRDAkd cerebellum, particularly within Purkinje cell somata. This deficit correlates with decreased expression and palmitoylation of the palmitoyltransferase DHHC3, while depalmitoylating enzymes remain unchanged. In vivo restoration of frataxin rescues GluR2 and DHHC3 levels and palmitoylation, supporting a mechanistic link between frataxin deficiency and disrupted lipid-dependent protein modification. Overall, this work identifies impaired GluR2 palmitoylation as a novel and selective molecular alteration in FRDA and highlights dysregulated lipid-dependent post-translational modification as key contributors to cerebellar synaptic vulnerability. These findings provide a framework for understanding early disease mechanisms and suggest potential targets for therapeutic intervention in Friedreich's ataxia

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Lynch, David R. Committee members: Robinson, Michael B.; Jordan-Sciutto, Kelly; Wilson, Robert B.; Ahrens-Nicklas, Rebecca

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247983286

Access Restriction:

Restricted for use by site license