Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…As novel insights into the progressive spinal cord pathology in this SCA2 model, Table 1 also highlights progressively reduced expression for several known neurodegeneration genes: firstly, Cdr1 (encoding Cerebellar Degeneration Related Protein 1, aka CDR62 or CDR34 or Yo-antigen) downregulation relates to its well-known autoimmune depletion as a cause of paraneoplastic ataxia [18] - it is interesting to note that Cdr1 expression is induced by the myelination factor Prion protein [172]; secondly, the Spinocerebellar Ataxia gene and voltage-gated potassium channel Kcna2 , which is preferentially expressed in afferent synapses onto the degenerating neurons [73, 229]; it is interesting to note that the parallel reduction of Kctd3 and Kctd9 affects two factors with potassium channel tetramerization domains; thirdly, the ALS disease gene Kif5a [20, 130] and its interactors Kif5b and Kif5c , which encode factors of axonal transport; Kif5a clusters with the progressive dysregulations of Uhmk1 (aka Ser/Thr-Protein kinase KIS) and Ina (aka internexin neuronal intermediate filament) in Table 1, since these factors relate to ribonucleoprotein and stress granule transport [24, 52, 108]. In the same context, the progressive expression downregulation of Hecw1 seems relevant, since this ubiquitination enzyme is responsible for the degradation of the ALS disease protein SOD1, is sequestrated into the cytosolic aggregates in ALS neurons, and its mutation leads to ALS-like phenotypes in mouse [123, 237]; fourth, the downregulation of Ano3 is important in view of its impact on tremor and dystonia [30, 196]; similarly, the reduced expression of Gnal encoding the G-protein G(olf) alpha, and of Rgs7bp encoding R7bp as general regulator of G-protein signaling appears relevant, in view of Gnal mutations triggering dystonia type 25 and the key role of R7bp in spinal afferents [51, 104, 141]; fifth, the insidious reduction of Scn4b mRNA seems relevant, given that Scn4b -null mice show motor coordination and balance deficits [158], that Scn4b expression depends on GABA-A signaling [150] and that Scn4b depletion was also observed in the striatum affected by polyglutamine-neurotoxicity due to Huntington’s disease mutation [139].…”

Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…The publicly available GWAS summary statistics for ALS included up to 20,806 cases and 59,804 controls of European ancestry. 21 All 20,806 probable or definite ALS patients diagnosed by a neurologist specializing in ALS according to the EI Escorial criteria were included in the case cohort study. 21…”

tRNA Queuosine Modification Enzyme Modulates the Growth and Microbiome Recruitment to Breast Tumors

“…Altered microbiome in tumors and intestines of nude mouse model. (a) Fluorescence in situ hybridization[4] staining with DAPI, EUB338, and Bfi826[20] of the tumors from the nude mice injected with wildtype and QTRT1-KO MCF7 breast cancer cells. Scale bar is 20 µm.…”