Exploration of SUMO2/3 Expression Levels and Autophagy Process in Fragile X-Associated Tremor/Ataxia Syndrome: Addressing Study Limitations and Insights for Future Research

Cells. 2023 Sep 26;12(19):2364. doi: 10.3390/cells12192364.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.

Keywords: FMR1 premutation; FXTAS; SUMO2/3; SUMOylation; autophagy; p62.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Ataxia / pathology
  • Autophagy
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome* / pathology
  • Humans
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Tremor* / genetics
  • Tremor* / metabolism
  • Tremor* / pathology
  • Ubiquitin / metabolism

Substances

  • Ubiquitin
  • Fragile X Mental Retardation Protein
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • FMR1 protein, human

Supplementary concepts

  • Fragile X Tremor Ataxia Syndrome

Grants and funding

This work was supported by the Instituto de Salud Carlos III (ISCIII) (through the projects PI17/01067, PI18/0049, PI21/00935, PI21/01085, PI20/0448), co-funded by the European Union, and AGAUR from the Autonomous Catalan Government (2021-SGR-01492). The CIBER de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III.