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  • Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels.

    24 October 2018

    Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein.

  • HspB8 mutation causing hereditary distal motor neuropathy impairs lysosomal delivery of autophagosomes.

    24 October 2018

    HspB8, a small heat-shock protein implicated in autophagy, is mutated in patients with distal hereditary motor neuropathy type II (dHMNII). Autophagy is essential for maintaining protein homeostasis in the central nervous system, but its role has not been investigated in peripheral motor neurons. We used a novel, multispectral-imaging flow cytometry assay to measure autophagy in cells. This assay revealed that over-expression of wild-type HspB8 in motor neuron-like NSC34 cells led to an increased co-localisation of autophagosomes with the lysosomes. By contrast, over-expression of mutant HspB8 resulted in autophagosomes that co-localised with protein aggregates but failed to co-localise with the lysosomes. A similar impairment of autophagy could also be demonstrated in peripheral blood mononuclear cells from two dHMNII patients with the HspB8(K141E) mutation. We conclude that defects in HspB8-mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease.

  • TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation.

    24 October 2018

    BACKGROUND: Mutations in the gene encoding TDP-43 have been identified in both familial and sporadic amyotrophic lateral sclerosis (ALS). METHODS: A mutation screen and copy number analysis in a motor neuron disease clinic cohort was conducted to characterise the genetic contribution of TARDBP. RESULTS: A novel missense mutation in a highly conserved region of TDP-43 was identified in a patient with sporadic ALS. The mutation is in close vicinity to previously identified changes. Copy number variation abnormalities were not detected. CONCLUSIONS: The findings stress the importance of TDP-43 in the pathogenesis of sporadic ALS.

  • The molecular genetics of non-ALS motor neuron diseases.

    24 October 2018

    Hereditary disorders of voluntary motor neurons are individually relatively uncommon, but have the potential to provide significant insights into motor neuron function in general and into the mechanisms underlying the more common form of sporadic Amyotrophic Lateral Sclerosis. Recently, mutations in a number of novel genes have been associated with Lower Motor Neuron (HSPB1, HSPB8, GARS, Dynactin), Upper Motor Neuron (Spastin, Atlastin, Paraplegin, HSP60, KIF5A, NIPA1) or mixed ALS-like phenotypes (Alsin, Senataxin, VAPB, BSCL2). In comparison to sporadic ALS these conditions are usually associated with slow progression, but as experience increases, a wide variation in clinical phenotype has become apparent. At the molecular level common themes are emerging that point to areas of specific vulnerability for motor neurons such as axonal transport, endosomal trafficking and RNA processing. We review the clinical and molecular features of this diverse group of genetically determined conditions and consider the implications for the broad group of motor neuron diseases in general.