Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood

Devon, Rebecca S.; Schwab, Claudia; Topp, Justin D.; Orban, Paul C.; Yang, Yijian; Pape, Terry D; Helm, Jeffrey; Davidson, Tara; Rogers, Daniel A.; Gros‐Louis, François; Rouleau, Guy A.; Horazdovsky, Bruce F.; Leavitt, Blair R.; Hayden, Michael R.

doi:10.1016/j.nbd.2004.10.002

Cited by 25 publications

(7 citation statements)

References 44 publications

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“…These ALS2 -deficient MNDs are commonly characterized by progressive degeneration of motor neurons in the central nervous system, indicating an important role for the ALS2 gene product (ALS2/alsin) in motor neuron survival and maintenance. Consistently, the ALS2 protein is expressed primarily in central nervous system neurons, including motor neurons of the cortex and spinal cord ( Devon et al, 2005 ; Otomo et al, 2003 ).…”

Section: Introductionmentioning

confidence: 96%

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

Kim

Nahm

et al. 2021

Journal of Cell Biology

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Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.

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Section: Introductionmentioning

confidence: 96%

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

Kim

Nahm

et al. 2021

Journal of Cell Biology

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“…Analysis of alsin tissue expression by immunohistochemistry2, 9 or in transgenic alsin:lacZ mice22 has shown that alsin is widely expressed in central nervous system neurons including spinal cord motoneurons. During mouse development, alsin protein could be detected as early as embryonic day E9.5, and its levels were found to increase until embryonic day E13.5 22. To generate a loss‐of‐function model for alsin, several groups have knocked out the mouse alsin gene by homologous recombination in embryonic stem cells.…”

mentioning

confidence: 99%

Alsin/Rac1 signaling controls survival and growth of spinal motoneurons

Jacquier

Buhler

Schäfer

et al. 2006

Annals of Neurology

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“…Furthermore, the relatively poor evolutionary conservation of the N-terminal region of ALSIN is also consistent with a structural rather than an important metabolic function of RCC1. 16 In conclusion, we have described a nonsense mutation in exon 10 of the ALS2 gene in two sibs of northwestern European origin. It is very likely that the mutation can be traced back to a common ancestor of the patients' parents who lived in the northern part of the Netherlands around 1750.…”

Section: A T C T a G A T T C C/t T/t T/t C/t A A A T C T A G A T T C mentioning

confidence: 70%

Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe

Verschuuren‐Bemelmans

Winter

Sival

et al. 2008

Eur J Hum Genet

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We describe a previously not recognized nonsense mutation in exon 10 of the ALS2 gene in two sibs with infantile-onset ascending spastic paralysis. The mutation predicts chain termination at amino-acid position 715 of the gene product ALSIN (p.Gln715X). The sibs' parents are descendants of a common ancestor who lived in the northern Netherlands during the eighteenth century. This is the first ALS2 mutation detected in northwestern Europeans. The findings emphasize that mutations in ALS2 also need to be considered in patients from northwestern Europe with early-onset spastic paralysis and amyotrophic or primary lateral sclerosis. In ALS2 both upper and lower motor neurons are affected, whereas neurodegeneration only involves upper motor neurons in JPLS and IAHSP. 5,6 Despite this difference in neuropathology, there is considerable clinical overlap of the major signs and symptoms in the three conditions, including spasticity of the limbs and dysarthria. The age of onset is during early childhood (first or second year), in the three disorders but appears to be somewhat later in ALS2 than in JPLS and IAHSP. The ALS2 gene is located on the long arm of chromosome 2 (2q33) and is composed of 34 exons.1,2 It can be transcribed into two alternative transcripts of 6.5 and 2.6 kb. The large transcript encodes ALSIN, a protein of 184 kD. ALSIN contains three putative guanine nucleotide exchange factor (GEF) domains, the N-terminal regulator of chromatin condensation (RCC1) domain, the central Db1 and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. European Journal of Human Genetics (2008) 16, 1407-1411 & 2008 Macmillan Publishers Limited All rights reserved 1018-4813/08 $32.00 www.nature.com/ejhgIt is not known whether the short transcript is physiologically translated into a functional polypeptide as well.To date, a total of 12 different mutations have been described in the ALS2 gene. All had occurred in people from Mediterranean countries and from Asia. Here we describe the first mutation in ALS2 in sibs from northwestern Europe. They are the children of consanguineous parents, who are descendants of a common ancestor who lived in the eighteenth century (around 1750) in the province of Friesland, in the northern part of the Netherlands. The findings are discussed in the context of published ALS2 mutations. Materials and methodsDNA extraction and sequencing of the 34 exons of ALS2 were performed according to standard procedures. Case reportsPatient 1, the proband, is the first child of healthy parents of Dutch descent. She was born at term after an uncomplicated pregnancy and delivery. At the age of 8 months she developed distal spasticity in her legs and axial hypotonia. She was never able to sit or stand without support. During the following 3 years, spastic diplegia slowly progressed to the upper extremities. Starting at age 5, she developed tetraplegia; with the lower extremities being more severely affected than the upper extremities, soft pseudobulbar speech, and dysp...

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Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood

Cited by 25 publications

References 44 publications

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

Alsin/Rac1 signaling controls survival and growth of spinal motoneurons

Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe

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