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. 2023 Oct 30;13(11):1531.
doi: 10.3390/brainsci13111531.

Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis

Jing Yang  1   2   3 , Cheng Xin  1   2   3 , Jia Huo  1   2   3 , Xin Li  1   2   3 , Hui Dong  1   2   3 , Qi Liu  1   2   3 , Rui Li  1   2   3 , Yaling Liu  1   2   3
Affiliations

Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis

Jing Yang et al. Brain Sci. .

Abstract

Background: Currently, there is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Many biomarkers have been proposed, but because ALS is a clinically heterogeneous disease with an unclear etiology, biomarker discovery for ALS has been challenging due to the lack of specificity of these biomarkers. In recent years, the role of autophagy in the development and treatment of ALS has become a research hotspot. In our previous studies, we found that the expression of RabGGTase (low RABGGTB expression and no change in RABGGTA) is lower in the lumbar and thoracic regions of spinal cord motoneurons in SOD1G93A mice compared with WT (wild-type) mice groups, and upregulation of RABGGTB promoted prenylation modification of Rab7, which promoted autophagy to protect neurons by degrading SOD1. Given that RabGGTase is associated with autophagy and autophagy is associated with inflammation, and based on the above findings, since peripheral blood mononuclear cells are readily available from patients with ALS, we proposed to investigate the expression of RabGGTase in peripheral inflammatory cells.

Methods: Information and venous blood were collected from 86 patients diagnosed with ALS between January 2021 and August 2023. Flow cytometry was used to detect the expression of RABGGTB in monocytes from peripheral blood samples collected from patients with ALS and healthy controls. Extracted peripheral blood mononuclear cells (PBMCs) were differentiated in vitro into macrophages, and then the expression of RABGGTB was detected by immunofluorescence. RABGGTB levels in patients with ALS were analyzed to determine their impact on disease progression.

Results: Using flow cytometry in monocytes and immunofluorescence in macrophages, we found that RABGGTB expression in the ALS group was significantly higher than in the control group. Age, sex, original location, disease course, C-reactive protein (CRP), and interleukin-6 (IL-6) did not correlate with the ALS functional rating scale-revised (ALSFRS-R), whereas the RABGGTB level was significantly correlated with the ALSFRS-R. In addition, multivariate analysis revealed a significant correlation between RABGGTB and ALSFRS-R score. Further analysis revealed a significant correlation between RABGGTB expression levels and disease progression levels (ΔFS).

Conclusions: The RABGGTB level was significantly increased in patients with ALS compared with healthy controls. An elevated RABGGTB level in patients with ALS is associated with the rate of progression in ALS, suggesting that elevated RABGGTB levels in patients with ALS may serve as an indicator for tracking ALS progression.

Keywords: Rab geranylgeranyltransferase subunit beta (RABGGTB); amyotrophic lateral sclerosis (ALS); macrophages; monocyte.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
ALS patient screening. ALS, amyotrophic lateral sclerosis.
Figure 2
Figure 2
RABGGTB expression in monocytes from healthy control and patients with ALS. (A) Analysis of peripheral blood classical-type monocytes by flow cytometry in healthy controls. (B) Analysis of peripheral blood classical-type monocytes by flow cytometry in patients with ALS. (C) Quantitative analysis of the RABGGTB concentration in peripheral blood monocytes of classical type. The statistical significance was determined using an unpaired t-test. ****, p < 0.0001. HC, healthy control; ALS, amyotrophic lateral sclerosis; RABGGTB, Rab geranylgeranyltransferase subunit beta.
Figure 3
Figure 3
Correlation between ALSFRS-R score or ΔFS and RABGGTB expression in monocytes from ALS patients. (A) Correlation between ALSFRS-R and the expression of RABGGTB in monocytes from ALS patients. (B) Correlation between ALSFRS-R and age in ALS. (C) Correlation between ΔFS and the expression of RABGGTB in monocytes from ALS patients. (D) Correlation between ΔFS and the duration of the disease in ALS.
Figure 4
Figure 4
Selection of patients with ALS in this study. ALS, amyotrophic lateral sclerosis.
Figure 5
Figure 5
RABGGTB expression in macrophages derived from healthy control and patients with ALS. (A) Phase-contrast microscopy images of macrophages differentiated with 20 ng/mL M-CSF for 4 days. Scale bars = 50 µm. (B) Phase-contrast microscopy images of macrophages differentiated with 20 ng/mL M-CSF for seven days. Scale bars = 50 µm. Immunofluorescence labeling of monocyte-derived macrophages for CD68 (red) and F4/80 (green). DAPI was used to stain nuclei (blue). Scale bars = 20 µm. (C) Immunofluorescence labeling for RABGGTB (gray/white), CD68 (red), and F4/80 (green) in monocyte-derived macrophages from patients with ALS and healthy controls. DAPI was used to stain nuclei (blue). Scale bars = 20 µm. (D) Quantitative analysis of RABGGTB levels in monocyte-derived macrophages from patients with ALS and healthy controls. The statistical significance was determined using an unpaired t-test. ****, p < 0.0001. ALS, amyotrophic lateral sclerosis; RABGGTB, Rab geranylgeranyltransferase subunit beta; M-CSF, macrophage colony-stimulating factor.
Figure 6
Figure 6
Correlation between ALSFRS-R score or ΔFS and RABGGTB expression in macrophages derived from monocytes. (A) ALSFRS-R is the revised ALS functional rating scale. (B) Correlation between ΔFS and the duration of the disease in ALS. (C) Correlation between ΔFS and the expression of RABGGTB in monocyte-derived macrophages.
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