The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1

Botzolakis, Emmanuel J.; Zhao, Jiali; Gurba, Katharine N.; Macdonald, Robert L.; Hedera, Peter

doi:10.1016/j.mcn.2010.08.012

Cited by 30 publications

(44 citation statements)

References 42 publications

(80 reference statements)

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“…Furthermore, we demonstrated recently that the normal function of C9ORF72, which contains a non-coding repeat expansion mutation in fALS, is to regulate endocytosis and autophagy, but this is dysregulated in ALS patient tissues [17]. Several ER-Golgi transport proteins are implicated in other motor neuron disorders, including atlastin [7] and seipin [28]. Disruption in ER-Golgi trafficking has also been described in spontaneous mouse mutants with motor phenotypes, pmn [59] and wobbler [60].…”

Section: Discussionmentioning

confidence: 99%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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Several diverse proteins are linked genetically/pathologically to neurodegeneration in amyotrophic lateral sclerosis (ALS) including SOD1, TDP-43 and FUS. Using a variety of cellular and biochemical techniques, we demonstrate that ALS-associated mutant TDP-43, FUS and SOD1 inhibit protein transport between the endoplasmic reticulum (ER) and Golgi apparatus in neuronal cells. ER-Golgi transport was also inhibited in embryonic cortical and motor neurons obtained from a widely used animal model (SOD1(G93A) mice), validating this mechanism as an early event in disease. Each protein inhibited transport by distinct mechanisms, but each process was dependent on Rab1. Mutant TDP-43 and mutant FUS both inhibited the incorporation of secretory protein cargo into COPII vesicles as they bud from the ER, and inhibited transport from ER to the ER-Golgi intermediate (ERGIC) compartment. TDP-43 was detected on the cytoplasmic face of the ER membrane, whereas FUS was present within the ER, suggesting that transport is inhibited from the cytoplasm by mutant TDP-43, and from the ER by mutant FUS. In contrast, mutant SOD1 destabilised microtubules and inhibited transport from the ERGIC compartment to Golgi, but not from ER to ERGIC. Rab1 performs multiple roles in ER-Golgi transport, and over-expression of Rab1 restored ER-Golgi transport, and prevented ER stress, mSOD1 inclusion formation and induction of apoptosis, in cells expressing mutant TDP-43, FUS or SOD1. Rab1 also co-localised extensively with mutant TDP-43, FUS and SOD1 in neuronal cells, and Rab1 formed inclusions in motor neurons of spinal cords from sporadic ALS patients, which were positive for ubiquitinated TDP-43, implying that Rab1 is misfolded and dysfunctional in sporadic disease. These results demonstrate that ALS-mutant forms of TDP-43, FUS, and SOD1 all perturb protein transport in the early secretory pathway, between ER and Golgi compartments. These data also imply that restoring Rab1-mediated ER-Golgi transport is a novel therapeutic target in ALS.

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Section: Discussionmentioning

confidence: 99%

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

et al. 2015

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“…It contains nine transmembrane domains and it is suggested to partake in cellular magnesium metabolism. Recent evidences show that NIPA1 and atlastin-1 are direct binding partners, since cellular distribution of atlastin-1/NIPA1 complexes is dramatically altered by HSP-causing mutations (Botzolakis et al, 2011). In addition, NIPA1 inhibits BMP signaling by promoting endocytosis and lysosomal degradation of the type II BMP receptor (BMPRII).…”

Section: Abnormal Cellular Signaling In Protein Morphogenesismentioning

confidence: 99%

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Giudice

Lombardi

Santorelli

et al. 2014

Experimental Neurology

289

278

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Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 72 spastic gait disease-loci and 55 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modeling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.

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“…NIPA1 encodes the protein NIPA1 [59] which is a direct binding partner of atlastin-1 [60]. Penetrance of NIPA1 mutations is high but age-dependent [2].…”

Section: Spg6mentioning

confidence: 99%

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

Finsterer

Löscher

Quasthoff

et al. 2012

Journal of the Neurological Sciences

249

213

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The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1

Cited by 30 publications

References 42 publications

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

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