SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1

Abstract

The predominant motor neuron disease in infants and adults is spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. SMA is caused by insufficient levels of the Survival Motor Neuron (SMN) protein, which operates as part of the multiprotein SMN complex that includes the DEAD-box RNA helicase Gemin3/DDX20/DP103. C9orf72, SOD1, TDP-43 and FUS are ranked as the four major genes causing familial ALS. Accumulating evidence has revealed a surprising molecular overlap between SMA and ALS. Here, we ask the question of whether Drosophila can also be exploited to study shared pathogenic pathways. Focusing on motor behaviour, muscle mass and survival, we show that disruption of either TBPH/TDP-43 or Caz/FUS enhance defects associated with Gemin3 loss-of-function. Gemin3-associated neuromuscular junction overgrowth was however suppressed. Sod1 depletion had a modifying effect in late adulthood. We also show that Gemin3 self-interacts and Gem3ΔN, a helicase domain deletion mutant, retains the ability to interact with its wild-type counterpart. Importantly, mutant:wild-type dimers are favoured more than wild-type:wild-type dimers. In addition to reinforcing the link between SMA and ALS, further exploration of mechanistic overlaps is now possible in a genetically tractable model organism. Notably, Gemin3 can be elevated to a candidate for modifying motor neuron degeneration.

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

“…This is suggested by the altered binding of mutant HSPB8 (p.K141N and p.K141E) to the RNA helicase DDX20 [449]. This component of the SMN (survival of motor neuron) complex and snRNPs is involved in transcriptional regulation and RNA processing, with functional connections to proteins associated with motor neuron degeneration, such as TDP-43 [450,451]. Along the same lines, decreased TDP-43 expression and altered splicing of TDP-43 target genes was recently reported in a muscle samples from patient with HSPB8-related neuromyopathy [440].…”

A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

“…Moreover, this study identified that NCDN and SMN interact within mobile cytoplasmic granules [ 76 ]. Interestingly, FUS and SMN are shown to share a common pathway in the context of neurobiology and ALS [ 6 , 7 , 23 , 88 ]. FUS is found to associate with the SMN complex through a direct interaction with SMN [ 88 ].…”

Protein network analysis to prioritize key genes in amyotrophic lateral sclerosis

“…DDX20 is associated with a neurogenerative disease SMA ( Charroux et al, 1999 ). Functional loss of DDX20 was observed in ALS on disruption of high-risk gene FUS ( Cacciottolo et al, 2019 ) . In modules-4, TP53 interacting proteins are majorly enriched with mRNA splicing function and highly associated with neoplasms diseases.…”