Researchers at the University of Antwerp have identified a new genetic cause of atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U)[1]. A CT dinucleotide repeat expansion in the GOLGA8 gene was found in approximately 60% of aFTLD-U cases, representing one of the strongest genetic associations reported for a sporadic neurodegenerative disease[1:1].
FTLD-FET is a spectrum of neurodegenerative diseases characterized by abnormal protein aggregates containing FET family proteins (FUS), TAF15, and EWS. The majority of FTLD cases are sporadic, with only about 10-20% having known genetic causes. This discovery adds GOLGA8 to the growing list of genes implicated in FTLD[1:2].
The GOLGA8 gene (also known as GOLGA8A or GOLGA8B in some annotations) encodes a member of the golgin family of proteins, which are involved in maintaining Golgi apparatus structure and function[2]. Golgins are large tethering proteins that organize Golgi membrane stacks and facilitate vesicle transport. GOLGA8 is primarily expressed in neuronal tissues and is localized to the Golgi apparatus, where it plays a role in protein sorting and trafficking.
The CT dinucleotide repeat expansion in GOLGA8 likely causes disease through several interconnected mechanisms:
RNA Foci Formation: Repeat-containing RNA forms toxic nuclear and cytoplasmic foci that sequester RNA-binding proteins, disrupting normal RNA processing[1:5]. This mechanism is similar to C9orf72 hexanucleotide repeat expansions seen in FTD/ALS.
RAN Translation: Repeat-associated non-ATG translation generates toxic dipeptide repeat proteins that can form inclusions and disrupt cellular function[1:6].
Somatic Expansion: The risk haplotype may be permissive to somatic CT repeat expansion in vulnerable neuronal populations, leading to age-dependent disease onset.
Gain-of-Function Toxicity: Unlike loss-of-function variants, the repeat expansion appears to confer a toxic gain-of-function without affecting native GOLGA8 protein expression.
| Gene | Repeat Type | Protein Aggregates | Disease |
|---|---|---|---|
| GOLGA8 | CT dinucleotide | TDP-43 | aFTLD-U |
| C9orf72 | Hexanucleotide | TDP-43 | FTD/ALS |
| FUS | None (mutations) | FUS | FTD/ALS |
| TAF15 | None (mutations) | TAF15 | FTD |
| EWS | None (mutations) | EWS | FTD |
GOLGA8 is the first FTLD-FET gene discovered to have a dinucleotide repeat expansion mechanism, suggesting that repeat expansions may be a more common pathogenic mechanism in FTLD than previously appreciated.