Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder that is characterized by retrograde axonal degeneration that primarily affects long spinal neurons. The disease is clinically heterogeneous, and there are >20 genetic loci identified. Here, we show a physical interaction between spastin and atlastin, two autosomal dominant HSP gene products. Spastin encodes a microtubule (MT)-severing AAA ATPase (ATPase associated with various activities), and atlastin encodes a Golgi-localized integral membrane protein GTPase. Atlastin does not regulate the enzymatic activity of spastin. We also identified a clinical mutation in atlastin outside of the GTPase domain that prevents interaction with spastin in cells. Therefore, we hypothesize that failure of appropriate interaction between these two HSP gene products may be pathogenetically relevant. These data indicate that at least a subset of HSP genes may define a cellular biological pathway that is important in axonal maintenance.

[1]  C. Blackstone,et al.  SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. , 2006, Human molecular genetics.

[2]  J. Luzio,et al.  Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. , 2006, Human molecular genetics.

[3]  C. Nolte,et al.  Early-onset ALS with long-term survival associated with spastin gene mutation , 2005, Neurology.

[4]  R. Vale,et al.  The Drosophila Homologue of the Hereditary Spastic Paraplegia Protein, Spastin, Severs and Disassembles Microtubules , 2005, Current Biology.

[5]  L. Santoro,et al.  The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy , 2005, Journal of Neurology.

[6]  G. Gundersen,et al.  Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing , 2005, The Journal of cell biology.

[7]  M. Pericak-Vance,et al.  Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations , 2004, Neurogenetics.

[8]  Noah W. Gray,et al.  Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor* , 2004, Journal of Biological Chemistry.

[9]  C. Blackstone,et al.  Cellular Localization, Oligomerization, and Membrane Association of the Hereditary Spastic Paraplegia 3A (SPG3A) Protein Atlastin* , 2003, Journal of Biological Chemistry.

[10]  S. Wharton,et al.  The Cellular and Molecular Pathology of the Motor System in Hereditary Spastic Paraparesis due to Mutation of the Spastin Gene , 2003, Journal of neuropathology and experimental neurology.

[11]  P. Bork,et al.  The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. , 2003, Genomics.

[12]  Michael T. McManus,et al.  A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference , 2003, Nature Genetics.

[13]  A. Tessa,et al.  SPG3A: An additional family carrying a new atlastin mutation , 2002, Neurology.

[14]  M. Pericak-Vance,et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). , 2002, American journal of human genetics.

[15]  E. Bertini,et al.  Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. , 2002, American journal of human genetics.

[16]  P. Bork,et al.  SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia , 2002, Nature Genetics.

[17]  M. Dalakas,et al.  Blockade of blocking antibodies in Guillain‐Barré syndromes: “Unblocking” the mystery of action of intravenous immunoglobulin , 2002, Annals of neurology.

[18]  A. Dürr,et al.  Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. , 2002, American journal of human genetics.

[19]  P. Hedera,et al.  Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia , 2001, Nature Genetics.

[20]  Bertrand Fontaine,et al.  Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia , 1999, Nature Genetics.

[21]  Sergio Cocozza,et al.  Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease , 1998, Cell.

[22]  S. Emr,et al.  The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function , 1998, The EMBO journal.

[23]  C. Sanderson,et al.  The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. , 2005, Human molecular genetics.

[24]  J. Melki,et al.  Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus. , 2003, Human molecular genetics.