The papers by Chen et al., 2003 and Emamian et al., 2003 offer compelling and complementary evidence for the significance of a single phosphorylation event—serine 776 of ataxin-1—on the pathogenesis of the polyglutamine-induced neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). Emamian et al. showed that, while wild-type ataxin-1[82Q] induced profound nuclear inclusions, the A776 mutant failed to form nuclear inclusions in transfected cells. Remarkably, the ataxin-1[82Q]-A776 transgenic mice also exhibited reduced nuclear inclusions in Purkinje cells, and concomitantly displayed very mild, if any, degeneration of these cells, compared to mice expressing wild-type ataxin-1[82Q].

In the same order of ideas, Chen et al. provided a molecular mechanism underlying the difference in the pathogenesis of mutant and wild-type ataxin-1. They found that 14-3-3e and z selectively bound to S776 phosphorylated ataxin-1, but not...  Read more

The papers by Chen et al., 2003 and Emamian et al., 2003 offer compelling and complementary evidence for the significance of a single phosphorylation event—serine 776 of ataxin-1—on the pathogenesis of the polyglutamine-induced neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). Emamian et al. showed that, while wild-type ataxin-1[82Q] induced profound nuclear inclusions, the A776 mutant failed to form nuclear inclusions in transfected cells. Remarkably, the ataxin-1[82Q]-A776 transgenic mice also exhibited reduced nuclear inclusions in Purkinje cells, and concomitantly displayed very mild, if any, degeneration of these cells, compared to mice expressing wild-type ataxin-1[82Q].

In the same order of ideas, Chen et al. provided a molecular mechanism underlying the difference in the pathogenesis of mutant and wild-type ataxin-1. They found that 14-3-3e and z selectively bound to S776 phosphorylated ataxin-1, but not to A776 ataxin-1, which resulted in stabilization of ataxin-1. The length of the polyglutamine tract is likely to enhance the stabilization of 14-3-3 with mutant ataxin-1. Chen et al. then identified Akt as the responsible kinase for this phosphorylation event. As an ultimate experiment, they utilized Drosophila genetics to suggest a synergistic role of the PI3K/Akt pathway and ataxin-1[82Q] in causing neurodegeneration. They propose that 14-3-3 stabilized Akt-phosphorylated mutant ataxin-1, thereby competing with factors mediating its degradation. These studies are exciting, as they provide the first insight for a dual role for Akt and 14-3-3 in the adult CNS and further shed light on the cell death processes in SCA1 pathogenesis.

Several issues remain to be determined in the future.

1. Is serine776 phosphorylation of ataxin-1 upregulated in SCA1 patients?

2. If so, how prevalent is it among the patients? What about the activity of the PI3K and/or Akt in the patients?

3. What is the role of nuclear inclusions in the disease? The A776 mutant fails to induce nuclear inclusions and is impaired in causing neurodegeneration. Thus, there is a perfect parallel between the appearance of inclusions and the pathogenesis of the disease. These findings somehow contradict the previous published results.

View all comments by Li-Huei Tsai

Phosphorylation of proteins is known to be associated with neurodegeneration, but the causal relationship between phosphorylation and neurodegeneration is unclear. Two articles by the laboratories of Harry Orr and Huda Zoghbi in the current Neuron and Cell, respectively, highlight the importance of phosphorylation in neurodegeneration. These labs have investigated the role of phosphorylation in neurodegeneration induced by expanded polyglutamine repeats in ataxin-1. Orr’s group noted that phosphorylation of Serine 776 of ataxin-1 was associated with inclusion formation and neurodegeneration. To test the causative role, they generated a mouse that carried an ataxin-1 gene that lacked Serine 776,

but contained an expanded polyglutamine repeat. The mice had substantially reduced toxicity. In their article, Zoghbi’s group looked at 14-3-3 protein, which binds phosphorylated proteins, and showed that 14-3-3 binds ataxin-1. Binding of 14-3-3 to ataxin-1 appears to slow its degradation. Together, these articles suggest that phosphorylation plays an important role in the accumulation...  Read more

Phosphorylation of proteins is known to be associated with neurodegeneration, but the causal relationship between phosphorylation and neurodegeneration is unclear. Two articles by the laboratories of Harry Orr and Huda Zoghbi in the current Neuron and Cell, respectively, highlight the importance of phosphorylation in neurodegeneration. These labs have investigated the role of phosphorylation in neurodegeneration induced by expanded polyglutamine repeats in ataxin-1. Orr’s group noted that phosphorylation of Serine 776 of ataxin-1 was associated with inclusion formation and neurodegeneration. To test the causative role, they generated a mouse that carried an ataxin-1 gene that lacked Serine 776,

but contained an expanded polyglutamine repeat. The mice had substantially reduced toxicity. In their article, Zoghbi’s group looked at 14-3-3 protein, which binds phosphorylated proteins, and showed that 14-3-3 binds ataxin-1. Binding of 14-3-3 to ataxin-1 appears to slow its degradation. Together, these articles suggest that phosphorylation plays an important role in the accumulation and toxicity of ataxin-1.

The significance of this work extends well beyond work on ataxin-1 because increased phosphorylation is associated with many proteins that accumulate in neurodegenerative diseases. For instance, the tau protein that accumulates to form neurofibrillary tangles shows increased phosphorylation at Ser 396, 404 and 202. Phosphorylation at Ser 129 is associated with accumulation of αa-synuclein in Lewy bodies (Fujiwara et al. 2002). The ability of phosphorylation to regulate the turnover of ataxin-1 suggests the possibility that phosphorylation also regulates the turnover of tau and α-synuclein. Indeed, 14-3-3 has been shown to bind α-synuclein, and 14-3-3 stimulates phosphorylation of tau protein Agarwal-Mawal, 2003; Ostrerova, 1999; Xu et al., 2002). In addition, 14-3-3 is present in both neurofibrillary tangles and Lewy bodies (Ubl et al. 2002; Layfield et al., 1996; Kawamoto et al., 2002). Taken together, these results suggest that protein phosphorylation plays a pivotal role in the pathophysiology of protein aggregation, perhaps regulating degradation of aggregation-prone proteins, and that 14-3-3 is a key regulator of this process.

References:
Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002 Feb;4(2):160-4. Abstract

Agarwal-Mawal A, Qureshi HY, Cafferty PW, Yuan Z, Han D, Lin R, Paudel HK. 14-3-3 Connects Glycogen Synthase Kinase-3beta to Tau within a Brain Microtubule-associated Tau Phosphorylation Complex. J Biol Chem. 2003 Apr 11;278(15):12722-8. Abstract

Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B. alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J Neurosci. 1999 Jul 15;19(14):5782-91. Abstract

Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA. Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nat Med. 2002 Jun;8(6):600-6. Abstract

Ubl A, Berg D, Holzmann C, Kruger R, Berger K, Arzberger T, Bornemann A, Riess O. 14-3-3 protein is a component of Lewy bodies in Parkinson's disease-Mutation analysis and association studies of 14-3-3 eta. Brain Res Mol Brain Res. 2002 Dec 16;108(1-2):33-9. Abstract

Layfield R, Fergusson J, Aitken A, Lowe J, Landon M, Mayer RJ. Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins. Neurosci Lett. 1996 May 3;209(1):57-60. Abstract

Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H. 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol. 2002 Mar;61(3):245-53. Abstract

View all comments by Benjamin Wolozin

Akt-1: The Good Guy Takes a Knock but Stays the Course

Opening scene: Akt protects its king (i.e., neuron) from dark forces. Protein kinase B (PKB or Akt) is a family of serine-threonine kinases with three isoforms. Following activation by either of the numerous receptor tyrosine kinases, Akt phosphorylates substrates bearing the R-x-R-x-x-S/T-F/L consensus motif. The first step in Akt’s activation is a conformational change upon binding of its Pleckstrin homology domain to the PI3K product, membrane phospholipid phosphatidylinositol 3,4,5-P3). Recruitment of Akt to the membrane is then a signal for the sequential phosposrylations of threonine 308 and serine 473 by the phosphoinositide-dependent protein kinases PDK1 and 2, respectively. Phosphorylation of both sites is required for Akt to become fully active.

Akt is a multifunctional gatekeeper molecule to many signaling events downstream of growth factor stimulation (Datta et al., 1999;   Read more

Akt-1: The Good Guy Takes a Knock but Stays the Course

Opening scene: Akt protects its king (i.e., neuron) from dark forces. Protein kinase B (PKB or Akt) is a family of serine-threonine kinases with three isoforms. Following activation by either of the numerous receptor tyrosine kinases, Akt phosphorylates substrates bearing the R-x-R-x-x-S/T-F/L consensus motif. The first step in Akt’s activation is a conformational change upon binding of its Pleckstrin homology domain to the PI3K product, membrane phospholipid phosphatidylinositol 3,4,5-P3). Recruitment of Akt to the membrane is then a signal for the sequential phosposrylations of threonine 308 and serine 473 by the phosphoinositide-dependent protein kinases PDK1 and 2, respectively. Phosphorylation of both sites is required for Akt to become fully active.

Akt is a multifunctional gatekeeper molecule to many signaling events downstream of growth factor stimulation (Datta et al., 1999; Lawlor et al., 2001). Cell proliferation, survival, and apoptosis are intimately regulated by Akt activity. Other cell processes under Akt control are glucose metabolism (e.g., through insulin signaling and PKBβ action) Cho et al., 2001), and vascular homeostasis (e.g., through integrin signaling and eNOS production) Shiojima et al., 2002). Downstream targets of Akt-orchestrated, inactivating phosphorylations are the pro-apoptosis molecules BAD, Forkhead, IKKα, GSK3-β and caspase 9, which account for the "good guy" role of Akt in cell survival. Frequently, Akt’s partner in sequestering these molecules is the chaperone protein 14-3-3.

In neurons (for example, those stressed by trophic factor withdrawal or excitotoxic injury), Akt’s position as a survival mediator is firmly established by these mechanisms, as well as another, novel one that involves hindrance of JNK activation by AKT (Dudek et al., 1997; Kim et al., 2002 ). It is relevant to note that mammalian cells have three Akt genes encoding corresponding isoforms, whereas Drosophila has but one. Thus, in fruit flies, mutation of Akt is lethal, whereas in mice, Akt-1 disruption causes growth retardation and organ-specific apoptosis, or a partial lethal phenotype. A large number of studies demonstrate, in various cell types, that constitutively active (CA)-Akt is sufficient to block cell death, and that a dominant-negative construct inhibits growth factor-induced survival.

Scene Two/New Villains Appear. Akt has just been cast as master regulator of antiapoptotic defenses, but the neurodegenerative disease plot thickens as intracellular and presumably misfolded proteins enter the stage as toxic "gain-of-function" attackers of cell survival. How will our hero fare?

In elegant back-to-back papers from the laboratories of Huda Zoghbi (Chen et al., 2003) and Harry Orr (Emamian et al., 2003), we learn that the PI3K/Akt signaling pathway enhances, not suppresses, the neurotoxicity of ataxin-1. This surprising role reversal pertains to 14-3-3 function, as well. In SCA-1, an inherited polyglutamine tract expansion in ataxin-1, leads to autosomal-dominant degeneration of cerebellar Purkinje cells. As in Huntington’s disease, accumulations of ataxin-1 are found as insoluble intranuclear inclusions. The nuclear inclusions per se are not required for disease progression (Cummings et al., 1999). In the Emamian paper, transfected CHO cells were used to isolate ataxin-30Q with a single phosphoserine residue (S776). Mutation of this site (A776) eliminated nuclear inclusions in cultured cells and transgenic mice, promoted ataxin partitioning into the soluble fraction, and resulted in disease-free mice, despite the persistent presence in the nucleus of ataxin-polyQ. The story here is complicated, but phosphorylation of serine appears to be unequivocally required for disease expression. Although P-S776 is linked to nuclear transport of ataxin-1, nuclear localization is not itself causative. Similarly, the polyQ tract is necessary but not sufficient for pathogenesis. The authors hypothesize that another protein, interacting specifically with P-S776, drives disease progression.

The Chen et al. paper is very convincing. Immunoprecipitation and protein purification techniques were applied in COS1 cells transfected with ataxin-1-82Q-S776 to identify 14-3-3 as its binding partner. Ataxin-1 has a 14-3-3 binding motif in which the critical S776 residue is embedded, and mutant of polyQ-ataxin that can’t be phosphorylated also was defective in 14-3-3 binding. In the presence of ataxin-S776-polyQ, 14-3-3 was recruited to yet larger nuclear inclusions. Increased steady-state levels of ataxin accompanied the aggravation of inclusions by 14-3-3. The authors demonstrated the effects of this interaction in vivo by showing that double-transgenic flies (14-3-3/ataxin polyQ) developed more severe retinal degeneration than did either transgene alone. Toward identifying the kinase responsible for ataxin-1 phosphorylation, the authors noted that this motif corresponded to a putative Akt consensus motif. In an in-vitro assay, purified Akt kinase phosphorylated a GST-ataxin-30Q fusion protein. The reaction was confirmed in cotransfected HeLa cells with constitutively active Akt. When GST-ataxin-30Q is incubated with immobilized 14-3-3, they associate only when ataxin is phosphorylated by Akt-1. Finally, co-IP of 14-3-3 was increased from transfections containing ataxin-1 and constitutively active Akt. Crossings of the SCA-1/ataxin-transgenic flies with Akt and PI3K markedly exacerbated the retinal phenotype. Interestingly and surprisingly, double-transgenic flies harboring either dPDK1 or dGSK3β genes showed no added effect. The authors conclude that 14-3-3 stabilizes Akt-phosphorylated, mutant ataxin levels, apparently sequestering it from protein degradation and thus accelerating disease. Since Akt accelerates SCA-1-type neurodegeneration, suppressing it may hold therapeutic value in this and possibly some pathogenic protein disorders, but could be deleterious in others.

To identify the kinase responsible for ataxin-1 phosphorylation, it was noted that the 14-3-3 motif corresponded to a putative Akt consensus motif. Using an in-vitro phosphorylation assay, a GST-ataxin-30Q fusion protein was phosphorylated by purified Akt kinase. The reaction was confirmed in HeLa cells transfected with CA-Akt. When GST-ataxin-30Q was incubated with immobilized 14-3-3, the two associated only when ataxin was phosphorylated by Akt-1. Finally, coimmunoprecipitation of 14-3-3 was increased in transfections containing ataxin-1 and CA-Akt.

These papers are important and thoroughly researched. They raise several interesting questions. If PI3K produces the same exacerbation of SCA-1 phenotype as Akt, why did the PKB-kinase, PDK1, have no effect? Since the PDK-1-catalyzed phosphorylation of threonine 308 is essential to Akt activation, and PDK-1 activity (with a putative PDK-2) is also required for the serine 473 step, one would expect it to have some effect in this system. The use of phospho-specific antibodies to these Akt sites in future work could show that it is the S473 phosphorylation that is pivotal.

It also remains to be worked out in which cellular compartments the soluble 14-3-3/ataxin complexes are toxic, since only a small fraction of 14-3-3 resides in the nuclear inclusions. The Chen et al. results will have even greater impact if reproduced in the transgenic SCA-1 mouse model of cerebellar involvement. For instance, crossing the SCA-1 with an Akt-1 knockout strain should lead to a straightforward answer.

Postlude or postmortem? In spite of these important studies, more articles have since continued to affirm the protective effect of Akt in other neurodegenerative models where a toxic protein is expressed. For instance, Fred Gage’s and Jeff Rothstein’s laboratory (see ARF related news story) delayed the progression of motor neuron disease (ALS) in the SOD1 mutant G93A mouse by delivering the neurotrophic factor IGF to the CNS. Intramuscular injection, followed by nervous uptake and retrograde transport of adeno-associated.virus (AAV)-IGF was associated with decreased apoptosis of spinal motor neurons and greater Akt activity.

Our own work in endothelial cells (Suhara et al., 2003) shows that viral-mediated expression of β-amyloid42 results in apoptotic death, and that this apoptosis is rescued by constitutively active Akt and aggravated by dominant-negative Akt. We chose endothelial cells because the Akt pathway is well-characterized in them, but have obtained the same results in other cell types. The mechanism of intracellular Aβ-induced death was in part through inhibition of Akt activation on both serine and threonine residues. The downstream effector of Aβ-induced death was activated GSK-3β, an Akt substrate and confirmed pro-apoptotic actor in a number of neurodegenerative conditions (Lucas et al., 2001; Jackson et al., 2002; Hetman et al., 2000; Takashima et al., 1998). Conversely, in the Chen work, GSKβ3 overexpression had no effect.

The work by Chen et al. does not exclude a normal neuroprotective role for Akt in the background; however, when a specific protein pathogen is involved (e.g., ataxin-1 polyQ), the detrimental action of Akt to stabilize the toxic molecule overwhelms its gentler side. The matter may indeed by simple: If the toxic protein has an Akt phosphorylation consensus site, the kinase will be pro-apoptotic by directly affecting the protein’s degradation. If, as suspected of most neurotoxic proteins (e.g., β-APP, Aβ, α-synuclein), there is no such site, Akt will promote survival. This hypothesis could be put to the test. For instance, the protein tau has a putative Akt site (Ksiezak-Reding et al., 2000). Actually, several regulatory molecules toggle between survival and degeneration depending on whether the cell is proliferating, quiescent, or differentiated. Likewise, proteasome inhibition may be pro- or antiapoptotic depending on what stage of the cell cycle the neuron is in. Even 14-3-3, which classically neutralizes pro-apoptotic proteins, may fall into the "ataxin camp" by abetting dopamine-mediated α-synuclein toxicity (Xu et al., 2002).

A major challenge for cell biologists working in neurodegeneration is to understand these signaling relationships as they change with specific cell subtype and in the context of misfolded proteins. Detailed road maps are needed to base therapy on this strategy so as not to inadvertently target bystander cell types for uncontrolled proliferation, developmental derangement, or death.

View all comments by Henry Querfurth

This paper by Subramaniam and colleagues presents some intriguing findings. For one thing, they identify the small G protein, Rhes, as defining a potential new class of non-traditional SUMO E3 ligases, thus opening a potential new window on the SUMOylation machinery. In addition, their study raises the possibility that Rhes activity may exacerbate the pathology of mutant Htt by preferentially causing its SUMOylation with consequences similar to those observed in Drosophila and cells. It will be interesting to see whether Rhes knockout mutations will suppress pathogenesis in mouse models of HD.

View all comments by J. Lawrence Marsh

We would like to comment on the interesting results of the recent study by Morfini et al. (1). Kinesin-1, a major microtubule motor that transports cargo in the plus-end direction of microtubules, is a heterotetramer consisting of two microtubule-binding, motor polypeptides (the heavy chains; KHCs) and two cargo-binding polypeptides (the light chains; KLCs). Being a soluble, cytoplasmic protein, kinesin-1 needs to bind the cargo in order to transport it. Therefore, recruitment of kinesin-1 to the cargo vesicle, and its release from it, are important regulatory steps of axonal transport. About 10 years ago, Scott Brady’s laboratory identified the first mechanism leading to the release of kinesin-1 from vesicles. According to this model, kinesin-1 is released through the action of the chaperone HSC70, and is nucleotide-dependent and NEM-sensitive (2). One year later, work from Larry Goldstein’s laboratory suggested that the premature release of kinesin-1 from cargo vesicles in neurons could impair fast axonal transport and lead to neuronal pathology and disease (3). Although the...  Read more

We would like to comment on the interesting results of the recent study by Morfini et al. (1). Kinesin-1, a major microtubule motor that transports cargo in the plus-end direction of microtubules, is a heterotetramer consisting of two microtubule-binding, motor polypeptides (the heavy chains; KHCs) and two cargo-binding polypeptides (the light chains; KLCs). Being a soluble, cytoplasmic protein, kinesin-1 needs to bind the cargo in order to transport it. Therefore, recruitment of kinesin-1 to the cargo vesicle, and its release from it, are important regulatory steps of axonal transport. About 10 years ago, Scott Brady’s laboratory identified the first mechanism leading to the release of kinesin-1 from vesicles. According to this model, kinesin-1 is released through the action of the chaperone HSC70, and is nucleotide-dependent and NEM-sensitive (2). One year later, work from Larry Goldstein’s laboratory suggested that the premature release of kinesin-1 from cargo vesicles in neurons could impair fast axonal transport and lead to neuronal pathology and disease (3). Although the mechanisms for the release of kinesin-1 from its vesicular cargos were incompletely understood at that time, the general idea that a premature release of the motor from its cargo could be at the core of the pathology in neurodegenerative diseases turned out to be correct, and generated an increased interest for research in this direction. Thus, work from the Brady and Busciglio laboratories identified at least two pathways for release of kinesin-1 from vesicles and halt of transport, which are likely to be factors leading to the axonal pathology and synaptic failure in Alzheimer’s disease (AD) (4-6).

Both pathways lead to phosphorylation of the KLCs, followed by detachment of kinesin-1 from the cargo, and impairment of vesicle transport. They are initiated by the addition of soluble Aβ oligomers, or expression of FAD-linked presenilin 1 variants, which trigger aberrant activation of casein kinase 2 or glycogen synthase 3β, which phosphorylate the KLCs. Why the phosphorylated kinesin-1 is released from vesicles is still not fully understood.

Along with AD, kinesin-1 is a target for abnormal phosphorylation in other neurodegenerative diseases, such as spinal and bulbar muscular atrophy (SBMA) and Huntington’s disease, as revealed by the studies from the Brady laboratory, including the work featured here (1, 7). However, in this case, the phosphorylation targets the KHCs, and the activated kinase that performs the phosphorylation is the cJun-N-terminal kinease (JNK). The phosphorylation of the KHCs leads to inhibition of binding of kinesin-1 to microtubules. As a result, the kinesin-1-cargo complex is released from the microtubules, and the transport is halted. These studies showed that the abnormal activation of JNK is triggered by the pathogenic, polyglutaminated, mutant proteins characteristic for polyglutamine (polyQ) expansion diseases: polyQ-androgen receptor in SBMA) (7), and polyQ-huntingtin in Huntingon’s disease(1). As the study by Morfini et al. (1) showed, polyQ-huntingtin activates JNK3, a neuron-specific JNK, that in turn phosphorylates KHC at a serine residue critical for the microtubule-binding function of kinesin-1. While in this case JNK3 is aberrantly activated by a disease factor, it is likely that, under normal conditions, the JNK-3 pathway contributes to the regulation of axonal transport.

Interestingly, in the squid axon system used in these studies, polyQ-huntingtin inhibits, not only the anterograde (kinesin-driven), but also the retrograde (cytoplasmic dynein-driven) fast axonal transport (1). It is not clear whether this inhibition of transport in both directions is due to the fact that kinesin-1 and cytoplasmic dynein interact and coordinate each other’s function (8), or is caused by a direct effect on the dynein machinery. Other studies showed that huntingtin regulates dynein-mediated vesicle transport, and can interact with both dynein and its accessory complex, dynactin (9, 10); however, the assays used by Morfini et al. (1) did not detect an interaction of huntingtin with dynein.

Certainly, other mechanisms, besides the release of the kinesin motor from the cargo or the microtubules, could contribute to the pathogenic processes in these neurodegenerative diseases. Other potentially damaging pathways that target the intracellular transport by affecting the cytoskeleton or the supply of ATP (by disrupting mitochondrial function) have been described (reviewed in (11)). Also, the activation of the kinases is likely to lead to the abnormal phosphorylation of other protein targets as well, with detrimental consequences for the function of neurons via mechanisms that may not involve abnormal axonal transport. For now, a picture emerges where the release of kinesin-1 from either cargo or microtubules, followed by impairment of axonal transport, becomes an important component of the pathogenic process in many neurodegenerative diseases. Therefore, it is the time to think of possibilities to correct the deficiencies, or to find means to enhance the disease-inflicted axonal transport.

References:
1. Morfini GA, You YM, Pollema SL, Kaminska A, Liu K, Yoshioka K, Björkblom B, Coffey ET, Bagnato C, Han D, Huang CF, Banker G, Pigino G, Brady ST. Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci. 2009 Jul;12(7):864-71. Abstract

2. Tsai MY, Morfini G, Szebenyi G, Brady ST. Release of kinesin from vesicles by hsc70 and regulation of fast axonal transport. Mol Biol Cell. 2000 Jun;11(6):2161-73. Abstract

3. Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. Abstract

4. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 2002 Feb 1;21(3):281-93. Abstract

5. Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, Ladu M, Busciglio J, Brady S. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5907-12. Abstract

6. Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003 Jun 1;23(11):4499-508. Abstract

7. Morfini G, Pigino G, Szebenyi G, You Y, Pollema S, Brady ST. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci. 2006 Jul;9(7):907-16. Abstract

8. Ligon LA, Tokito M, Finklestein JM, Grossman FE, Holzbaur EL. A direct interaction between cytoplasmic dynein and kinesin I may coordinate motor activity. J Biol Chem. 2004 Apr 30;279(18):19201-8. Abstract

9. Caviston JP, Ross JL, Antony SM, Tokito M, Holzbaur EL. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10045-50. Abstract

10. Zala D, Colin E, Rangone H, Liot G, Humbert S, Saudou F. Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet. 2008 Dec 15;17(24):3837-46. Abstract

11. De Vos KJ, Grierson AJ, Ackerley S, Miller CC. Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci. 2008;31:151-73. Abstract

View all comments by Zoia Muresan
View all comments by Virgil Muresan

The paper by Molero et al. is an excellent study that builds on previous work to steadily support a somewhat heretic notion: that degenerative brain disorders are, in fact, neurodevelopmental disorders in which the key pathoetiology is that of abnormal development. Studies supporting this theory have come from several areas of research (both clinical and basic science) as well as from a variety of diseases including Alzheimer's, Parkinson's, Huntington's, and the polyglutamine diseases such as the spinal cerebellar ataxias (SCAs). One study that supports this theory (Serra et al., 2006) shows that in a mouse model of SCA type 1, the motor phenotype and histologic abnormalities of the cerebellum are much more severe if the mutant protein, ataxin 1 (ATXN1), is expressed during development. If it is expressed after development, the phenotype and histology are substantially less. Therefore, not only is abnormal development a part of the etiology, it is a vital part. Also, as mentioned in the Molero article, clinical studies of subjects with Huntington's, who are known to have a...  Read more

The paper by Molero et al. is an excellent study that builds on previous work to steadily support a somewhat heretic notion: that degenerative brain disorders are, in fact, neurodevelopmental disorders in which the key pathoetiology is that of abnormal development. Studies supporting this theory have come from several areas of research (both clinical and basic science) as well as from a variety of diseases including Alzheimer's, Parkinson's, Huntington's, and the polyglutamine diseases such as the spinal cerebellar ataxias (SCAs). One study that supports this theory (Serra et al., 2006) shows that in a mouse model of SCA type 1, the motor phenotype and histologic abnormalities of the cerebellum are much more severe if the mutant protein, ataxin 1 (ATXN1), is expressed during development. If it is expressed after development, the phenotype and histology are substantially less. Therefore, not only is abnormal development a part of the etiology, it is a vital part. Also, as mentioned in the Molero article, clinical studies of subjects with Huntington's, who are known to have a polyglutamine expanded gene but are over 20 years from developing the disease, show brain abnormalities that are more likely due to abnormal development rather than prolonged degeneration (Paulsen et al., 2006 and Nopoulos et al., 2007).

It is time for the field of degenerative brain disorders to have a conceptual frame-shift. In particular, if these diseases are to be ”cured” or prevented, then focusing on the degenerative phase of the disease may not be as effective as understanding the origins of the disorders in the context of abnormal development.

References:
Serra, H G, L Duvick, T Zu, et al., RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 2006. 127(4): 697-708. Abstract

Paulsen, J S, V A Magnotta, A E Mikos, et al., Brain structure in preclinical Huntington's disease. Biol Psychiatry 2006. 59(1): 57-63. Abstract

Nopoulos, P, V A Magnotta, A Mikos, H Paulson, N C Andreasen, and J S Paulsen, Morphology of the cerebral cortex in preclinical Huntington's disease. Am J Psychiatry 2007. 164(9): 1428-34. Abstract

View all comments by Peggy Nopoulos