FAS promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5-4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3-5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4-2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3-10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS

Novel systemic delivery of a peptide-conjugated antisense oligonucleotide to reduce α-synuclein in a mouse model of Alzheimer's disease

Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α-synuclein (α-syn) and amyloid beta (Aβ). Misfolded and aggregated α-syn has been implicated in neurological disorders such as Parkinson's disease, and Dementia with Lewy Bodies, but less so in Alzheimer's Disease (AD), despite the fact that accumulation of α-syn has been confirmed in over 50% of postmortem brains neuropathologically diagnosed with AD. To date, no therapeutic strategy has effectively or consistently downregulated α-syn in AD. Here we tested the hypothesis that by using a systemically-delivered peptide (ApoB11) bound to a modified antisense oligonucleotide against α-syn (ASO-α-syn), we can downregulate α-syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. Our results demonstrate that monthly systemic treatment with of ApoB11:ASO α-syn beginning at 6 months of age reduces expression of α-synuclein in the brains of 9-month-old AD mice. Downregulation of α-syn led to reduction in Aβ plaque burden, prevented neuronal loss and astrogliosis. Furthermore, we found that AD mice treated with ApoB11:ASO α-syn had greatly improved hippocampal and spatial memory function in comparison to their control counterparts. Collectively, our data supports the reduction of α-syn through use of systemically-delivered ApoB11:ASO α-syn as a promising future disease-modifying therapeutic for AD

<i>FAS</i> and <i>FASL</i> gene polymorphisms in patients with GBS and healthy controls.

<p><i>FAS</i> and <i>FASL</i> gene polymorphisms in patients with GBS and healthy controls.</p

Serum levels of sFas and sFasL in severely and mildly affected patients with GBS.

<p>Severity of disease was assessed using the GBS disability score, a GDS ≥ 3 was defined as severely affected and ≤ 2, as mildly affected. The Whisker-box plots indicate the minimum, maximum and median values; *<i>P</i> < 0.05, Mann–Whitney <i>U</i>-test.</p

<i>FAS</i> and <i>FASL</i> promoter polymorphisms in patients with GBS stratified by clinical and immunological features.

<p><i>FAS</i> and <i>FASL</i> promoter polymorphisms in patients with GBS stratified by clinical and immunological features.</p

Association of mannose-binding lectin 2 gene polymorphisms with Guillain-Barré syndrome

Complement activation plays a critical role in the pathogenesis of Guillain-Barré syndrome (GBS), a debilitating immune-mediated neuropathy. Mannose-binding lectin (MBL) is a complement activation factor of lectin pathway which as genetic host factor may influence the susceptibility or severity of GBS. We investigated the frequency of MBL2 promoter (− 550H/L and − 221X/Y) and functional region (exon 1 A/O) polymorphisms and their association with disease susceptibility, clinical features and serum MBL among GBS patients (n = 300) and healthy controls (n = 300) in Bangladesh. The median patient age was 30 years (IQR: 18–42; males, 68%). MBL2 polymorphisms were not significantly associated with GBS susceptibility compared to healthy controls. HL heterozygosity in GBS patients was significantly associated with mild functional disability at enrolment (P = 0.0145, OR, 95% CI 2.1, 1.17–3.82). The HY, YA, HA and HYA heterozygous haplotypes were more common among mildly affected (P = 0.0067, P = 0.0086, P = 0.0075, P = 0.0032, respectively) than severely affected patients with GBS. Reduced serum MBL was significantly associated with the LL, OO and no HYA variants and GBS disease severity. No significant association was observed between MBL2 polymorphisms and electrophysiological variants, recent Campylobacter jejuni infection or anti-ganglioside (GM1) antibody responses in GBS. In conclusion, MBL2 gene polymorphisms are related to reduced serum MBL and associated with the severity of GBS

<i>FAS</i> promoter polymorphisms and serum sFas level are associated with increased risk of nerve damage in Bangladeshi patients with Guillain-Barré syndrome

<div><p>Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (<i>FAS</i>) and Fas ligand (<i>FASL</i>) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in <i>FAS</i> (-1377G/A and -670A/G) and <i>FASL</i> (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The <i>FAS</i> -670 AG heterozygous (<i>P</i> = 0.0005, OR = 2.5, 95% CI = 1.5–4.2) and GG homozygous (<i>P</i> = 0.0048, OR = 2.6, 95% CI = 1.3–5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The <i>FAS</i> -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (<i>P</i> = 0.0002, OR = 1.9, 95% CI = 1.4–2.7) and also in patients with the axonal subtype than demyelinating subtype (<i>P</i> < 0.0001, OR = 4.8, 95% CI = 2.3–10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (<i>P</i> < 0.0001) and anti-ganglioside antibody-positivity (<i>P</i> = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; <i>P</i> < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; <i>P</i> = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (<i>P</i> = 0.0406). In conclusion, this study indicates <i>FAS-FASL</i> promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS.</p></div

Associations between <i>FAS</i> -1377/-670 haplotypes and GBS.

<p>Associations between <i>FAS</i> -1377/-670 haplotypes and GBS.</p

Demographic, clinical and electrophysiological characteristics of the 300 patients with GBS and 300 healthy controls.

<p>Demographic, clinical and electrophysiological characteristics of the 300 patients with GBS and 300 healthy controls.</p