ELOVL1 – Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a complex neurodegenerative disorder primarily characterised by postural instability and vertical gaze palsy. Recent whole‐genome sequencing studies have expanded our understanding of PSP genetics, uncovering multiple susceptibility loci. Notably, variants in ELOVL1 (HGNC:14418) have emerged as one of the significant signals associated with PSP, suggesting a role in disease risk (PMID:39152475). This association builds on the observation that PSP is a multifactorial disorder influenced by both common single nucleotide variants and structural alterations in the genome.

Large‐scale analyses including a cohort of 1,718 PSP cases and 2,944 controls have provided independent evidence for the involvement of ELOVL1. The genetic association is supported by robust statistical findings from two separate studies (PMID:39152475; PMID:38234807), where the consistent association across diverse populations reinforces its clinical significance. Although the study design did not focus on Mendelian inheritance, the aggregated data underline the impact of common and structural variation in predisposing individuals to PSP.

In terms of genetic evidence, the observed association spans a spectrum of variants, including common single nucleotide changes and structural variants. For example, while not directly reported in the PSP-specific cohorts, the variant c.494C>T (p.Ser165Phe) in ELOVL1—frequently described in the functional characterization of this gene—illustrates the gene’s vulnerability to perturbations that affect fatty acid elongation. This variant was originally identified in studies addressing neurocutaneous and myelination disorders, providing a tangible link between ELOVL1 disruptions and neurological dysfunction (PMID:29496980).

Functional studies on ELOVL1 have revealed its critical role in the elongation of very-long-chain fatty acids, which are essential for maintaining lipid homeostasis in neural tissues. Although these investigations have primarily centered on neurocutaneous syndromes and myelination defects rather than PSP per se, the underlying biology suggests that altered lipid composition may contribute to neurodegeneration. Such assays, including fatty acid profiling and murine model analyses, confirm that ELOVL1 dysfunction can impair myelin integrity, thereby potentially creating a biological milieu conducive to diseases like PSP.

Notably, no significant conflicting evidence has emerged to dispute the association between ELOVL1 and PSP. The genetic observations have been replicated and are consistent across independent cohorts, while the experimental data in related neurological disorders further substantiate the gene’s functional importance. However, direct experimental validation in PSP models remains an important goal for future research, as the current functional evidence is derived from studies on overlapping but distinct phenotypes.

In conclusion, the integration of robust genetic association data with functional studies of ELOVL1 underscores its potential role in the pathogenesis of PSP. Additional research is expected to further delineate the mechanistic pathways and refine risk assessment. Key take‑home: ELOVL1 is a promising candidate for informing PSP diagnostic decision‑making and for future therapeutic investigations.

References

• Molecular neurodegeneration • 2024 • Whole‑genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy PMID:39152475
• medRxiv • 2024 • Whole‑Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy PMID:38234807

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