Abstract
Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer's (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p = 8*10-5), three-fold between 62-72 years (p = 0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p = 0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman's rho = 0.31, p = 0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p = 0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0144-4) contains supplementary material, which is available to authorized users.
Highlights
Multiple sclerosis (MS) has classically been considered as an auto-immune disease of the white matter
Kif21b mRNA expression was assessed in the white matter of 11 non-demented controls (NDC) and 16 MS patients (Additional file 1: Table S3) and we found that kif21b was approximately ten-fold increased in MS compared with NDC
Kif21b is significantly increased in Alzheimer’s disease (AD) patients compared with MS and NDC
Summary
Multiple sclerosis (MS) has classically been considered as an auto-immune disease of the white matter. The grey matter component of the pathology receives increasing attention, especially because axonal and neuronal degeneration occur already early in the disease [1]. This area of research received an impulse by novel MRI techniques to visualize grey matter lesions [2]. A large genome wide association study (GWAS) in MS patients identified 57 single nucleotide polymorphisms (SNP) associated with an increased risk to develop MS. Most of the (SNP) have important functions in immune cells, mainly in T-cell biology [3].
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