Limits...
Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Aeinehband S, Lindblom RP, Al Nimer F, Vijayaraghavan S, Sandholm K, Khademi M, Olsson T, Nilsson B, Ekdahl KN, Darreh-Shori T, Piehl F - PLoS ONE (2015)

Bottom Line: In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects.Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation.These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

No MeSH data available.


Related in: MedlinePlus

BuChE activity, but not AChE activity, correlates with levels of C3 and NFL.BuChE activity was not different between MS patients and controls at the group level, however, with a large spread within groups (A). A highly significant correlation between BuChE activity and C3 levels is evident (B). Also, BuChE activity correlated with levels of NFL (C) and demonstrates a close to significant trend for correlation to EDSS (D). Interestingly, AChE activity differs between MS patients and controls (E), but lacks correlation to C3 at the individual level (F). *p = < 0.05; ** = p < 0.01; *** = p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4383591&req=5

pone.0122048.g002: BuChE activity, but not AChE activity, correlates with levels of C3 and NFL.BuChE activity was not different between MS patients and controls at the group level, however, with a large spread within groups (A). A highly significant correlation between BuChE activity and C3 levels is evident (B). Also, BuChE activity correlated with levels of NFL (C) and demonstrates a close to significant trend for correlation to EDSS (D). Interestingly, AChE activity differs between MS patients and controls (E), but lacks correlation to C3 at the individual level (F). *p = < 0.05; ** = p < 0.01; *** = p < 0.001.

Mentions: The genetic link between local expression of BuChE and C3 after experimental nerve injury provided a rationale to determine BuChE activity in the clinical samples [19,34]. In addition, activity of AChE, the other main ACh hydrolyzing enzyme [35], was determined. Enzymatic activity and protein levels displayed a high degree of correlation for BuChE (p<0.0001, R2 = 0.887). At the group level, BuChE activity in MS patients did not differ from controls (Fig 2A). However, in individual samples BuChE activity significantly correlated to both C3 and NFL in the MS group (Fig 2B and 2C), and displayed a trend for correlation to EDSS (Fig 2C and 2D). In contrast, AChE enzymatic activity at the group level was significantly decreased in MS patients as compared to OND (Fig 2E). On an individual level AChE activity did not correlate neither to C3 nor NFL (Fig 2F). On the contrary, there was a trend for a negative correlation between AChE activity and EDSS (p = 0.086, R2 = 0.064), thus, opposite to the pattern of BuChE. MS patients carrying the BuChE-K allele displayed an 8% lower BuChE activity than non-carriers, however, the difference was not statistically different.


Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Aeinehband S, Lindblom RP, Al Nimer F, Vijayaraghavan S, Sandholm K, Khademi M, Olsson T, Nilsson B, Ekdahl KN, Darreh-Shori T, Piehl F - PLoS ONE (2015)

BuChE activity, but not AChE activity, correlates with levels of C3 and NFL.BuChE activity was not different between MS patients and controls at the group level, however, with a large spread within groups (A). A highly significant correlation between BuChE activity and C3 levels is evident (B). Also, BuChE activity correlated with levels of NFL (C) and demonstrates a close to significant trend for correlation to EDSS (D). Interestingly, AChE activity differs between MS patients and controls (E), but lacks correlation to C3 at the individual level (F). *p = < 0.05; ** = p < 0.01; *** = p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383591&req=5

pone.0122048.g002: BuChE activity, but not AChE activity, correlates with levels of C3 and NFL.BuChE activity was not different between MS patients and controls at the group level, however, with a large spread within groups (A). A highly significant correlation between BuChE activity and C3 levels is evident (B). Also, BuChE activity correlated with levels of NFL (C) and demonstrates a close to significant trend for correlation to EDSS (D). Interestingly, AChE activity differs between MS patients and controls (E), but lacks correlation to C3 at the individual level (F). *p = < 0.05; ** = p < 0.01; *** = p < 0.001.
Mentions: The genetic link between local expression of BuChE and C3 after experimental nerve injury provided a rationale to determine BuChE activity in the clinical samples [19,34]. In addition, activity of AChE, the other main ACh hydrolyzing enzyme [35], was determined. Enzymatic activity and protein levels displayed a high degree of correlation for BuChE (p<0.0001, R2 = 0.887). At the group level, BuChE activity in MS patients did not differ from controls (Fig 2A). However, in individual samples BuChE activity significantly correlated to both C3 and NFL in the MS group (Fig 2B and 2C), and displayed a trend for correlation to EDSS (Fig 2C and 2D). In contrast, AChE enzymatic activity at the group level was significantly decreased in MS patients as compared to OND (Fig 2E). On an individual level AChE activity did not correlate neither to C3 nor NFL (Fig 2F). On the contrary, there was a trend for a negative correlation between AChE activity and EDSS (p = 0.086, R2 = 0.064), thus, opposite to the pattern of BuChE. MS patients carrying the BuChE-K allele displayed an 8% lower BuChE activity than non-carriers, however, the difference was not statistically different.

Bottom Line: In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects.Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation.These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

No MeSH data available.


Related in: MedlinePlus