Eight families with the rare neurodegenerative disorder Perry syndrome share mutations in the cellular transport protein dynactin, according to a study published online January 11 in Nature Genetics. The region disrupted by the mutations normally acts as a “parking brake,” affixing the motor complex tightly to its microtubule track. The authors, led by Matthew Farrer of the Mayo Clinic in Jacksonville, Florida, speculate that the mutant protein careens helter-skelter along microtubules and fails to properly deliver its cargo.

Perry syndrome is an exceedingly rare disorder that affects people in their mid-forties and kills them within two to 10 years. It initially manifests with severe depression; one-third of people with the diagnosis have attempted suicide, Farrer said. Parkinsonism and motor difficulties then occur, followed by significant weight loss and difficulty breathing.

Perry syndrome is inherited as an autosomal-dominant trait. To identify a genetic root for the disorder, Farrer’s Mayo Clinic colleague Zbigniew Wszolek assembled an international team of researchers to collect genealogies and blood samples from eight families with the syndrome, from Canada, the United Kingdom, France, Japan, Turkey, and the United States. Farrer guessed that a few other families carry a gene for Perry syndrome, but not many. Fifty to 100 affected people worldwide would be a generous estimate, he said.

Genomewide screening showed that all eight families had mutations in the DCTN1 gene, leading to substitutions (G71R, G71E, G71A, T72P, or Q74P) within the same four amino acid stretch of the dynactin subunit p150glued. These mutations did not show up in nearly 1,500 control subjects. Dynactin is a multi-subunit protein complex that partners with the molecular motor dynein to modulate cargo delivery across the cell (for review, see Schroer, 2004). The dynein/dynactin complex carts lipids and proteins, Golgi-associated and endocytic vesicles, endosomes, pigment granules, mitochondria, and occasionally even the nucleus around the cell. It also carries cellular components along the axon in neurons. The dynactin region containing the mutations, called the CAP-Gly domain, binds fast to microtubules, as well as to the microtubule-binding proteins CLIP170 and end-binding protein 1 (EB1).

The current study marks the latest in a long line of papers to implicate dynein/dynactin function in neurodegenerative disease. Dysfunction of intraneuronal trafficking may be a common feature in neurodegenerative disease, Farrer suggested. For example, the p150glued subunit associates with tau, linking it to frontotemporal dementia and parkinsonism (Magnani et al., 2007). Huntingtin, the protein whose mutant form causes Huntington disease, appears to bind to dynein and help it drag vesicles around the cell (Caviston et al., 2007).

The p150glued subunit has also been linked with motor neuron disease. Point mutations in DCTN1 (T1249I, M571T, and R785W) have been found in patients clinically diagnosed with ALS (Münch et al., 2004). Notably, the DCTN1 G59S mutation—also within the CAP-Gly domain—lowers the protein’s affinity for microtubules and EB1, and causes specific degeneration of motor neurons (Levy et al., 2006). The G59S mutation causes adult-onset motor neuron disease with symptoms including vocal fold paralysis, muscle weakness, and atrophy. Two recent papers described dynactin dysfunction and motor neuron disease in mice heterozygous for the DCTN1 G59S mutation; homozygotes were not viable (Laird et al., 2008; Lai et al., 2007).

Using in-vitro microtubule binding assays, Farrer and colleagues showed that the mutant p150glued has an abnormally low affinity for these intracellular train tracks. A second microtubule-binding domain in p150glued, which has predominantly basic residues, has previously been shown to hook up with microtubules, but it lets the protein slide back and forth along the polymer (Culver-Hanlon et al., 2006). The CAP-Gly “parking brake” region is required to strengthen the dynactin-microtubule interaction and allow the motor to move directionally. Farrer imagines the following functional consequences of the dynactin mutations in Perry syndromes: under the basic domain’s control, but with faulty brakes, the motor complex may wander aimlessly along the microtubule and deliver its cargo to the wrong cellular location, if at all.

However, more work is needed to prove that it is indeed dynein/dynactin trafficking that causes disease in people with the Perry syndrome mutations. Alternatively, it could be the CAP-Gly domain’s altered interaction with CLIP170 or EB1, or the mutant protein complex could simply be unstable and tagged for degradation.

One mystery is that although the G59S and Perry disease mutations both reside in the CAP-Gly domain of p150/glued, they cause disease in completely different cell types. While G59S affects motor neurons, the Perry mutations hit the substantia nigra, a region affected in Parkinson disease. “It’s amazing that both of these diseases show such cell-type specificity,” said Erika Holzbaur of the University of Pennsylvania in Philadelphia. “It’s not what you would expect.” For the Perry mutations, Farrer said, it may be short-range trafficking that is affected. That would explain why motor neurons, with their meter-long axons, remain healthy in people with Perry syndrome.

The two classes of mutation also share TDP-43 proteinopathy in affected cells. The G59S mutation leads to large, vesicle-like aggregates with TDP-43. Perry mutations cause smaller, punctate TDP-43 aggregates. It is not clear yet whether TDP-43 is involved in disease pathology, or is merely a “tombstone” that marks affected cells, Farrer said.

One possible explanation for two different conditions caused by such nearby mutations, Farrer said, is that G59 is deep within the CAP-Gly domain, while the residues mutated in Perry syndrome reside on the protein’s surface. The G59S mutation, then, might have more dire consequences for protein structure, leading to bigger aggregations. Farrer and Holzbaur plan to collaborate on the mechanism of the Perry mutations. Because dynein/dynactin transport so many different cellular components, that’s no easy task, Holzbaur said. “We have a long list to work through, to find where the key defect is.”

Farrer is already pondering potential treatments for Perry syndrome, such as RNA interference with DCTN1, although he noted such therapies would be far in the future. The rarity of the disorder hardly makes it a tempting target for drug developers. However, finding the molecular root of the disorder is the first step.—Amber Dance.

Reference:
Farrer MJ, Hulihan MM, Kachergus JM, Dächsel JC, Stoessl AJ, Grantier LL, Calne S, Calne DB, Lechevalier B, Chapon F, Tsuboi Y, Yamada T, Gutmann L, Elibol B, Bhatia KP, Wider C, Vilariño-Güell C, Ross OA, Brown LA, Castanedes-Casey M, Dickson DW, Wszolek ZK. DCTN1 mutations in Perry syndrome. Nat Genet AOP 11 January 2009. Abstract

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References

Paper Citations

  1. . Dynactin. Annu Rev Cell Dev Biol. 2004;20:759-79. PubMed.
  2. . Interaction of tau protein with the dynactin complex. EMBO J. 2007 Oct 31;26(21):4546-54. PubMed.
  3. . Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10045-50. PubMed.
  4. . Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology. 2004 Aug 24;63(4):724-6. PubMed.
  5. . A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation. J Cell Biol. 2006 Feb 27;172(5):733-45. PubMed.
  6. . Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. J Neurosci. 2008 Feb 27;28(9):1997-2005. PubMed.
  7. . The G59S mutation in p150(glued) causes dysfunction of dynactin in mice. J Neurosci. 2007 Dec 19;27(51):13982-90. PubMed.
  8. . A microtubule-binding domain in dynactin increases dynein processivity by skating along microtubules. Nat Cell Biol. 2006 Mar;8(3):264-70. PubMed.
  9. . DCTN1 mutations in Perry syndrome. Nat Genet. 2009 Feb;41(2):163-5. PubMed.

Further Reading

Papers

  1. . Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003 May 2;300(5620):808-12. PubMed.
  2. . Dynein-dynactin complex subunits are differentially localized in brain and spinal cord, with selective involvement in pathological features of neurodegenerative disease. Neuropathol Appl Neurobiol. 2008 Feb;34(1):88-94. PubMed.
  3. . Mutant dynactin in motor neuron disease. Nat Genet. 2003 Apr;33(4):455-6. PubMed.
  4. . DCTN1 mutations in Perry syndrome. Nat Genet. 2009 Feb;41(2):163-5. PubMed.
  5. . Dynactin is necessary for synapse stabilization. Neuron. 2002 May 30;34(5):729-41. PubMed.
  6. . Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron. 2002 May 30;34(5):715-27. PubMed.

News

  1. Dynein—Mutations Put the Brakes on Aggregate Clearance
  2. Role of the Motor in Motor Neuron Diseases
  3. Dynamitin in Motor Neurons: Dynamite for ALS Research?
  4. Paris: Intracellular Traffic and Neurodegenerative Disorders

Primary Papers

  1. . DCTN1 mutations in Perry syndrome. Nat Genet. 2009 Feb;41(2):163-5. PubMed.