Sci. Aging Knowl. Environ., 7 May 2003
Vol. 2003, Issue 18, p. pe10
[DOI: 10.1126/sageke.2003.18.pe10]

PERSPECTIVES

Defects in Dynein Linked to Motor Neuron Degeneration in Mice

Julie Andersen

The author is at the Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, USA. E-mail: jandersen{at}buckinstitute.org

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/18/pe10

The most common neurodegenerative disorders in humans involve the progressive loss of motor neuron populations [for review, see (1)]. They include amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although causative genetic mutations have been identified for a small subset of these ultimately fatal diseases, the molecular basis for most forms remains a mystery. In the 2 May 2003 issue of Science, Hafezparast and colleagues (2) present exciting new data suggesting a role for mutations in the molecular motor component dynein as a causative agent in selective motor neuron degeneration in two lines of mice. These findings may have major implications for related human pathologies.

The mouse mutants, Legs at odd angles (Loa) and Cramping 1 (Cra1), originally arose as offspring from N-ethyl-N-nitrosourea-treated male mice in two independent mutagenesis experiments. Heterozygous animals from these lines were found to manifest similar age-related progressive losses in both muscle tone and locomoter ability, suggesting a dominant pattern of inheritance. Pathologically, these animals display a progressive apoptotic loss of spinal cord anterior horn alpha neurons (motor neurons that control muscle function in the extremities) and altered muscle fiber composition. Homozygous animals are more severely affected than the heterozygotes, dying within 24 hours postnatally because of an inability to move or feed. Analysis of late embryonic tissue from homozygous mice in these mutants revealed the presence of Lewy body-like perinuclear inclusions that contained several proteins, including ubiquitin, superoxide dismutase 1 (Sod1), CDK5, and neurofilament (NF) (Fig. 1); these proteins are also found in similar inclusions called Bunina bodies that have been observed in certain slowly progressive forms of human ALS (3). These proteins are involved in various functions, including ridding cells of damaged proteins and detoxification of the products of oxidative stress.



View larger version (101K):
[in this window]
[in a new window]
 
Fig. 1. Inclusion body formation with positive immunoreactivity for NF (A) and Sod1 (B) is observed in surviving motor neurons of Loa/Loa embryos. [Photo courtesy of (2)]

 
Subsequent analysis revealed that both Loa and Cra1 involve allelic missense point mutations in the dynein heavy chain 1 (Dnchc1) gene. Dnchc1 encodes a subunit of the molecular motor cytoplasmic dynein, which is involved in the intracellular movement of vesicles and protein complexes along microtubules. Cytoplasmic dynein participates in axonal retrograde transport (a cellular system involved in the movement of "cargoes," such as vesicles and protein complexes, along the axon toward the cell body), nuclear motility, and various aspects of Golgi function. The Loa and Cra1 mutations were found affect conserved residues in the protein that are involved in hetero- or homodimerization of the DNCHC protein to form the motor complex, which also includes two intermediate-chain dyneins and other components of the complex required for its activity. These mutations appear to reduce the performance of the complex in situations of cellular stress (for example, when the Golgi complex is disrupted by treatment with nocodazole). Golgi disruption is also observed in human ALS, as well as in transgenic models of the disease (4).

Most strikingly, these Dnchc mutations appear to affect the neuronal-specific rather than ubiquitous functions of the corresponding protein, including the migration of facial motor neuron cell bodies in the hindbrain; the efficiency of axonal branching and elongation within target areas; and fast axonal transport, specifically in spinal cord motor neurons, as detected by the movement of fluorescently tagged tetanus toxin. These phenomena appear to be due to a dominant negative effect of these mutations as opposed to a loss of function of the gene product, because targeted knockouts of the gene in mice have previously been found to result in early embryonic lethality in homozygous animals and no apparent pathologies in the heterozygotes (5). Compromised migration of facial motor neurons could contribute to the subsequent inability of homozygous Loa mice to suckle and thus explain their early neonatal death. Facial motor weakness caused by impairment of motor neurons of the brain stem is a classical feature of both SBMA and some forms of ALS. The authors further speculate that the age-related progression of motor neuron loss in the heterozygous animals may be due to impaired dynein-dependent retrograde fast axonal transport, which could impinge on the continued supply of trophic factors such as nerve growth factor needed for maintenance of these cells. With respect to Golgi function, steady-state morphology and positioning were normal in the Loa and Cra1mutant mice, and only rebuilding of the peri-centrosomal Golgi complex after nocodazole treatment was impaired.

These findings may have major implications for human motor neuron disorders. Although their molecular bases are not well understood, these diseases are among the most common forms of neurodegeneration. Are similar mutations in genes encoding dynein or other proteins that affect retrograde axonal transport involved in any of the known human motor neurodegenerative diseases? It appears very likely. A recently identified mutation in dynactin, part of another complex that interacts with dynein, results in an SBMA-like syndrome in a human kindred, including facial and extremity muscle weakness. This finding suggests that such mutations may exist that are involved in other human motor neurodegenerative diseases (6). Other evidence also suggests that this may be the case. Retrograde transport of NF is dynein-dependent, and the abnormal accumulation of NF in neuronal cell bodies and proximal axons is a common pathological feature of ALS (7). Sod1 transport to the cell body may also require dynein (8). Mutations in SOD1 are found in a subset of ALS patients, and recent evidence has suggested that mouse mutants recapitulating this form of the disorder demonstrate slowed axonal transport (9). One important difference, however, between the effects of the SOD1 mutations in heterozygous mice and in the human disease states is that, although life span is unaffected in the rodent models, motor degeneration results in a major decrease in the life span of humans with such conditions. Whether this manifestation of the mutation is species-specific is unclear.

Another important issue broached in this paper is how mutations in widely expressed genes result in the selective degeneration of motor neurons. Certain forms of SBMA are linked to triplet repeats in the androgen receptor gene, and, as mentioned above, mutations in SOD1 are known to account for a subset of familial forms of ALS. How subtle heterozygous allelic mutations in the Loa and Cra1 mice affect only the neuronal functions of dynein is unclear. However, the ability to study the specific effects of these particular mutations in these mouse models may shed some light on this quandary.


May 7, 2003
  1. D. W. Cleveland, J. D. Rothstein, From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806-819 (2001).[CrossRef][Medline]
  2. M. Hafezparast, R. Klocke, C. Ruhrberg, A. Marquardt, A. Ahmad-Annuar, S. Bowen, G. Lalli, A. S. Witherden, H. Hummerich, S. Nicholson et al., Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808-812 (2003). [Abstract/Free Full Text]
  3. K. Tsuchiya, S. Shintani, H. Nakabayashi, K. Kikugawa, R. Nakano, C. Haga, I. Nakano, K. Ikeda, S. Tsuji, Familial amyotrophic lateral sclerosis with onset in bulbar sign, benign clinical course, and Bunina bodies: A clinical, genetic, and pathological study of a Japanese family. Acta Neuropathol. 100, 603-607 (2000).[CrossRef][Medline]
  4. A. Stieber, J. O. Gonatas, J. Collard, J. Meier, J. Julien, P. Schweitzer, N. K. Gonatas, The neuronal Golgi apparatus is fragmented in transgenic mice expressing a mutant human SOD1, but not in mice expressing the human NF-H gene. J. Neurol. Sci. 173, 63-72 (2000).[CrossRef][Medline]
  5. A. Harada, Y. Takei, Y. Kanai, Y. Tanaka, S. Nonaka, N. Hirokawa, Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein. J. Cell Biol. 141, 51-59 (1998).[Abstract/Free Full Text]
  6. I. Puls, C. Jonnakuty, B. H. LaMonte, E. L. Holzbaur, M. Tokito, E. Mann, M. K. Floeter, K. Bidus, D. Drayna, S. J. Oh et al., Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455-456 (2003).[CrossRef][Medline]
  7. M. E. Gurney, Transgenic-mouse model of amyotrophic lateral sclerosis. N. Engl. J. Med. 331, 1721-1722 (1994).[CrossRef][Medline]
  8. J. P. Julien, Amyotrophic lateral sclerosis. Unfolding the toxicity of the misfolded. Cell 104, 581-591 (2001).[CrossRef][Medline]
  9. T. L. Williamson, D. W. Cleveland, Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci. 2, 50-56 (1999).[CrossRef][Medline]
Citation: J. Andersen, Defects in Dynein Linked to Motor Neuron Degeneration in Mice. Sci. SAGE KE 2003, pe10 (7 May 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/18/pe10








Science of Aging Knowledge Environment. ISSN 1539-6150