Hot-spot KIF5A mutations cause familial ALS

Abstract

Brenner et al. show that mutations in a C-terminal hotspot of kinesin-5A (KIF5A) can cause a classical ALS phenotype. Experiments using patient-derived cell lines suggest haploinsufficiency as the molecular genetic mechanism. This underlines the relevance of intracellular transport processes for ALS, and is important for clinico-genetic diagnosis and counselling.

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].…”

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…Regarding the newly identified genes (Table 1), KIF5A pathogenic variants appear to be specific for the European population (Brenner et al, 2018). Among the new genes, the FTO genomic variants are founder mutations for the Greek population (Mitropoulos, Katsila, Patrinos, & Pampalakis, 2018).…”

“…In Asian populations, the most common pathogenic variant is in SOD1 (FALS 30.0%, SALS 1.5%), and then it is in FUS (FALS 6.4%, SALS 0.9%), followed by the hexanucleotide repeats in C9ORF72 (FALS 2.3%, SALS 0.3%) and by pathogenic variants in TDP‐43 (FALS 1.5%, SALS 0.2%; Zou et al., ). Regarding the newly identified genes (Table ), KIF5A pathogenic variants appear to be specific for the European population (Brenner et al., ). Among the new genes, the FTO genomic variants are founder mutations for the Greek population (Mitropoulos, Katsila, Patrinos, & Pampalakis, ).…”

“…However, in some cases the position of the pathologic variant may underlie the development of a certain phenotype. Missense mutations at the N‐terminal domain of KIF5A are reported to cause monogenic spastic paraplegia (HSP10) and Charcot–Marie–Tooth disease type 2 (CMT2), whereas mutations at the C‐terminal domain are linked with ALS (Brenner et al., ). It should be noted that although the pathogenic variants found in SOD1 , C9ORF72 , TARDBP‐43 , FU S, CFAP410 ( C21ORF2 ), CCNF , TBK1 , CHCHD10 , MATR3 , TUBA4A , HNRNPA1 , HNRNPA2B1, PFN1 , SQSTM1 , UBQLN2 , ATXN2 , OPTN , SPG11 ( SPG11S ), VCP , ANG , ELP3 , CHMP2B , VAPB , DCTN1 , ALS2 , SETX , and NEFH genes are well validated in ALS cases (Chia, Chiò, & Traynor, ), the others need further validation because they are either very rare or very new.…”

A stochastic model that explains axonal organelle pileups induced by a reduction of molecular motors

“…These diseases are often characterized by local axonal swellings containing accumulations of axonally transported cargoes both in human patients [13][14][15][16] and in animal models [17][18][19][20]. In many familial cases, these diseases are caused by mutations in proteins involved in intracellular transport, including mutations that impair the activity of the motor proteins [21][22][23][24][25][26][27]. However, little & 2018 The Author(s) Published by the Royal Society.…”