Summary

Benjamin Wolozin led this live discussion on 17 January 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
Live discussion held on 17 January 2002.

Participants: Benjamin Wolozin, Michael Schlossmacher, Ted Dawson, June Kinoshita, Shai Shoham.

Note: The transcript has been edited for clarity and accuracy.

June: Hello and welcome everyone on this snowy morning! Let's get started.

Benjamin Wolozin: Hello Michael - can you comment on what you see as the role of parkin in ubiquitinating synuclein?

Michael Schlossmacher: Regarding the interaction of parkin and α-synuclein: α-synuclein is probably just one of parkin's many substrates. It is the one most interesting to us because of the link to autosomal dominant aS-linked PD and sporadic PD.

Benjamin Wolozin: I guess one of the questions that must be frequently posed to you, Michael, is whether the glycosylated form of α-synuclein plays a role in PD. For instance by initiating aggregation.

Michael Schlossmacher: We don't yet know whether it mediates aggregation. We wish to study this, but don't have sufficient amounts of it yet.

Ted Dawson: {enters}

Benjamin Wolozin: Hi Ted!!

Michael Schlossmacher: Hideki Shimura just joined me; we are a 2-man team now.

June: Hello Ted and Hideki!

Ted Dawson: Hello everyone.

Benjamin Wolozin: Michael and Hideki - do you think the absence of glycosylated α-synuclein in Lewy bodies is significant or just a sensitivity issue?

Michael Schlossmacher: We are working on raising an antibody that is specific for the glycosylated form of α-synuclein and does not cross-react with regular α-synuclein p16. Only then can we judge whether it is present or not.

guest4 {enters}

June: Hello Guest 4, who are you?

guest4: Yuan Bin, I am a rotatation PhD student from Wolozin's lab.

Shai Shoham: Hello, this is Shai Shoham

June: Welcome Shai. Where are you logging in from today?

Shai Shoham: Jerusalem, Israel

June: Just before this discussion, Michael Schlossmacher sent a comment to Ben's background text for this discussion. It is posted below Ben's text. Let's pick up his thoughts.

Benjamin Wolozin: In responding to Michael's comment-I agree entirely. We are seeing this with multiple neurodegenerative diseases, where inherited forms of the illness suggest common mechanisms of pathogenesis for the disease in general.

Michael - Very good points in your comment.

June: Do you agree that the nomenclature should be changed to reflect this view?

Benjamin Wolozin: I agree with the nomenclature change somewhat. However, one issue is that late-onset PD has Lewy body pathology or other inclusions that are generally not present in ARJP. I have addressed this in the second paragraph of my comment.

Ted Dawson: I would not support a change in the nomenclature at this early juncture of characterizing genetic PD. It is still instructive to discuss AR-PD and AR-JP. As we learn more about the genetics we may define PD based upon an individual's mutation.

Benjamin Wolozin: Michael, I like the idea of heritable forms of PD. I just think that there might be a difference between cases where parkin is active vs. cases where parkin is inactive. Ted's point relates to this.

Michael Schlossmacher: In reference to your previous thought, Ben, if glycosylated α-synuclein p22 is involved in Lewy body formation, we would expect little to be present in non-ubiquitinated form. This is in press at the American Journal of Pathology.

Benjamin Wolozin: Yup, glycosylated a-SP22 makes sense for LB if it is there.

Benjamin Wolozin: Ted - what would you say about the role of synphilin and CDCrel1 in PD?

Ted Dawson: Regarding synphilin and the synaptice vesicle-associated protein CDCrel-1 (Zang et al. 2000), I think that synphilin plays a potentially important role as it links non-glycosylated synuclein and parkin in a common pathogenic pathway in PD. Obviously more work needs to be done to clarify its role in PD (see ARF news story).

Michael Schlossmacher: I predict that there will be several adaptor proteins for the parkin-E3 complex in human brain, as is the case with other ubiquitin-ligase complexes. The binding partners Ted identified may represent such adaptors.

Benjamin Wolozin: There are an increasing number of proteins that bind α-synuclein. So you think that perhaps synphilin is one of several proteins present in the Lewy bodies that might bind non-ubiquitinated synuclein?

Ted Dawson: The Arg275Trp mutation described in the Farrer paper (Farrer et al., 2001) is a partially active mutant as described in our Nature Medicine paper (see ARF news story). Thus it is the exception that proves the rule that parkin is required for Lewy body formation

Benjamin Wolozin: Ted - I agree that parkin is probably required for Lewy body formation. Hence the abundance of ubiquitin in Lewy bodies. Do people think that ubiquitination might help to sequester proteins that cannot be degraded by the proteasome?

Ted Dawson: It is possible, but how the system works to send proteins to Lewy bodies versus the proteasome is a puzzle.

Shai Shoham {leaves}

Benjamin Wolozin: Does anyone know whether it has been definitively shown whether or not α-synuclein in Lewy bodies is ubiquitinated?

Ted Dawson: I have not seen any convincing data. In fact, there seems to be a dissociation between ubiquitin immunreactivity and synuclein immunoreactivity when using confocal dissection.

Benjamin Wolozin: Interesting. Is one more peripheral than the other, or something else?

Michael Schlossmacher: Our immunohistochemical data suggest that parkin and UbcH7 localize to the core, whereas most of the immunoreactivity for α-synuclein is in the periphery, at least by conventional Immunohistochemistry.

Ted Dawson: They seem to be in different microcompartments. It could be a problem with antibody penetration or epitope recognition. Synphilin is in the core.

Benjamin Wolozin: What about ubiquitin?

Michael Schlossmacher Ubiquitin also is predominantly, but not exclusively, in the core as per Gai et al., 2000. Ben, why do you doubt the presence of ubiquitinated aS in Lewy body extracts (See Trojanowski et al, 1998.)

Benjamin Wolozin: I don't doubt the question, I'm just trying to bring out people's opinions for the discussion.

June: This is perhaps slightly off topic, but are the Lewy bodies seen in PD identical at the molecular level to those seen in AD? For that matter, are Lewy bodies in the various subtypes of PD all created equal?

Benjamin Wolozin: Cortical Lewy bodies have a different structure than Lewy bodies in the substantia nigra, but I don't know whether cortical Lewy bodies in diseases like dementia with Lewy body disease (DLBD) differ from those in AD.

Michael Schlossmacher: Based on my impression, I'd say that the formation of Lewy bodies in AD, PD, and DLBD rests on the interaction of some key players, but that they vary to some extent between diseases and within neuroanatomic regions.

Ted Dawson Is Pael-r in Lewy bodies? (See ARF news story.)

Michael Schlossmacher Rumor has it that Pael-R is in Lewy bodies, yes.

Benjamin Wolozin: Pael-R is an interesting question because it is an ER protein. Parkin is known to affect the ER stress response, which raises the issue of the role of ER in PD. We have looked at ER stress markers in PD, but don't see evidence of elevation more than in controls.

Ted Dawson: So is parkin dysfunction involved in sporadic PD?

Benjamin Wolozin: This is different than asking if Pael-r is in Lewy bodies. But the involvement of Pael-r inherently raises the question of whether ER stress plays a role in PD.

Michael Schlossmacher: Ted, two papers on polymorphisms in parkin in sporadic PD out of Japan would suggest that (Satoh & Kuroda, 1999; Wang et al., 1999).

Benjamin Wolozin: Ted, I think Michael's comment about Farrer's work is apt. It certainly suggests a role, right? Although Farrer's case is by no means sporadic PD, but it is a late-onset case - hence the comment.

Ted Dawson: So parkin dysfunction might involve different mechanisms of cellular toxicity depending on the mutation?

Terry Bowers {enters}

Ted Dawson Yes, but this will take some time to prove.

Michael Schlossmacher I'd predict that there is a common denominator for parkin dysfunction-related cellular toxicity based on other E3 ligase work.

Ted Dawson: What is your favorite common denominator?

Michael Schlossmacher: I don't have one yet.

Benjamin Wolozin: Here is something somewhat far afield, but perhaps worth bringing up for discussion. What I find particularly interesting, recently, is the comparison of mechanisms of death in Huntington's vs. other diseases. It seems that recent results in Huntington's point to a mechanism relating to gene transcription, whereas many of us in AD and PD have focused on free radicals and/or proteasomal dysfunction. (See for example, ARF news story, ARF news story.) Any thoughts?

Michael Schlossmacher: Excellent point. I think dysregulation of transcriptional control is subject of ongoing PD research work now, too.

Ted Dawson: I have to go to a meeting so I must sign off. Best regards to everyone.

Benjamin Wolozin: Ciao!

Benjamin Wolozin: The Huntington's stuff is fascinating, and there are two issues raised by it. One is the question of whether the inclusion is good or bad. My sense is that many have postulated that inclusions in both HD and PD are protective because they sequester small toxic aggregates, but here is a mechanism whereby sequestration is bad. The second point is the connection between transcription and neuroprotection/growth factor signaling. (See ARF news story.) Any thoughts from people?

Benjamin Wolozin: Mike, when you say parkin dysfunction, do you discriminate between gain or loss of function, with respect to a hypothetical common denominator?

Yuan Bin: Unlike in ARJD, sporadic PD shows a normal parkin, so parkin might not be the key. Maybe the key point is other proteins.

Michael Schlossmacher: Brown and Goldstein and many other examples have taught us that the relentless pursuit of altered genotypes in human disorders is at the root of better understanding of complex biochemical pathways.

Benjamin Wolozin: Yuan, this is always a question, but I agree with Mike because historically investigating inherited forms of disease has been very productive.

June: I just want to note that our hour is up. Thank you all very much! We will be circulating a transcript, so you will all have a chance to carry forward the discussion via e-mail.

Michael Schlossmacher: Yes, thanks for your thoughts, and bye all.

Benjamin Wolozin: June, bye. Mike and Ted - thanks so much for participating. You guys are doing great work. Thanks to everyone else for adding comments or listening in.

Nico And thanks Mike, Ted and everyone else!

guest4: Bye and thanks, everyone.

Nico: Bye, number 4, bye everyone!

Terry Bowers: Since the science is over we can chat on other subjects, yes?

Terry Bowers: Can't believe I've missed this website…

Background

Background Text
By Benjamin Wolozin

Mutations in parkin are associated with a Parkinson-like syndrome, termed autosomal recessive juvenile parkinsonism (ARJP) (1). This syndrome resembles Parkinson's disease (PD) in that patients suffer from degeneration of dopaminergic neurons in the substantia nigra and a resulting paucity of movement. The syndrome differs from PD in multiple significant ways. AJRP is a genetic illness, whereas PD is most strongly associated with environmental factors (although it does appear to have an underlying genetic component). ARJP generally occurs in young individuals, whereas PD generally occurs in people over age 60. Finally, AJRP lacks Lewy bodies, which are a pathological hallmark of PD (2).

Despite the differences between AJRP and PD, the link between mutations in parkin and selective degeneration of neurons of the substantia nigra, suggest that understanding the biology of parkin could provide important insights into the mechanism of degeneration of dopaminergic neurons in PD. Indeed, several studies have already shown that parkin is involved in the pathophysiology of PD because parkin accumulates in Lewy bodies and axonal spheroids in PD, and mutations in parkin have been observed in some cases of classic PD (2, 3, 4).

Parkin turns out to be a ubiquitin ligase, which provides an immediate link to ubiquitination, which is a process that has previously been implicated in neurodegeneration because most pathological structures in neurodegenerative diseases are ubiquitinated (5, 6). For those of you not intimately acquainted with ubiquitin metabolism, I have adapted a simple diagram describing the ubiquitin-dependent proteasomal cascade that was generated by Ferrell and colleagues and is available on the web at, http://www.proteasome.com/publications/Ferrell/diagram1.htm (figure 1) (7).

The cell constantly turns over proteins. This is important for two reasons. First, the presence of rapid protein turnover provides a convenient mechanism for regulating protein levels, and thereby regulating protein function. The cyclin proteins, which regulate cell cycle, are regulated in this manner. A second important function is in elimination of damaged proteins, such as oxidized or denatured proteins such as occur in abundance in neurodegenerative diseases. The cell targets proteins for destruction by adding a small protein sequence, termed ubiquitin, which tags the protein for rapid destruction by a large, multi-subunit organelle, termed the proteasome (7). The ubiquitin-proteasomal cycle involves at least five steps and three proteins: 1) ubiquitin is activated by coupling it to a protein termed E1. 2) The E1 then transfers the ubiquitin to E2, termed ubiquitin conjugase. 3) The E3 ubiquitin ligase binds selectively to a target protein, and transfers multiple ubiquitins from E2 proteins to the substrate. 4) The ubiquitinated protein is bound by the proteasome and degraded. 5) The ubiquitin is removed and recycled by a protein termed ubiquitin C-terminal hydrolase (UCHL).

It should be noted that target specificity is achieved by the action of both E2, which consists of a family of at least nine separate proteins, and E3, which has numerous family members. The general process of protein tagging is actually more complicated because there are other proteins that resemble ubiquitin, such as SUMO and NEDD8, that can also be added to proteins by other ligases and target proteins to other organelles (8). Three different lines of evidence implicate ubiquitination in PD. Lewy bodies contain abundant ubiquitin, parkin is a cause of many cases of familial PD, and a mutation in UCHL1 has also been associated with PD on one kindred. The link between parkin, ubiquitination, and PD, has sparked immense interest because of the potential insights into mechanism of degeneration of dopaminergic neurons. More specifically, the proteins whose turnover is dependent on parkin might play a fundamental role in the process of degeneration of dopaminergic neurons.

Two new articles each identify a novel parkin substrate that could be important for the pathophysiology of PD. In a paper just published in Cell, Imai and colleagues have used a yeast two-hybrid screen to identify a protein, termed Pael-R, that binds parkin (9). Pael-R is a protein resident in the endoplasmic reticulum, and is a substrate for ubiquitination by parkin. They also show that levels of Pael-R are elevated in brains of patients with ARJP. This is important because particular stressors appear to make Pael-R unfold, and the unfolded protein is toxic, which provides a potential explanation for why loss of the mutations in parkin that cause ARJP might lead to degeneration of dopaminergic neurons in ARJP. Whether this is also involved in the degeneration of dopaminergic neurons in PD remains to be determined, but this is certainly one hope that drives the study of parkin. The second paper, by Shimura, Schlossmacher and colleagues addresses α-synuclein, which is a protein that has already been implicated in PD (10). Mutations in α-synuclein are associated with PD in 2-3 different kindreds (there is some debate as to whether two particular kindreds are actually related), and α-synuclein is the principal component of Lewy bodies, which are the pathological hallmark of PD.

The mechanism of accumulation of α-synuclein has been a subject of intense research. The protein seems to spontaneously aggregate, but aggregation also appears to be stimulated by exogenous factors, such as the mitochondrial toxin rotenone, free radicals, and metals, such as iron. The other major component of Lewy bodies is ubiquitin. Given that parkin is a ubiquitin ligase, it seems quite possible that parkin is responsible for ubiquitinating α-synuclein. This hypothesis is suggested by two previous studies, and one study in review, which demonstrate that parkin and α-synuclein co-localize in Lewy bodies (2, 4, 11). The current article, addresses this question directly, and shows that parkin binds to a novel 22 kDa glycosylated form of α-synuclein, termed aSp22. Parkin is able to ubiquitinate this form of α-synuclein in vitro. They are also able to show a functional link in vivo because brains from patients who died from ARJP, which lack active parkin, have higher levels of aSp22.

This work provides a direct link between parkin and α-synuclein, but it is a link that raises as many questions as it answers. One curious aspect of this story is that they do not demonstrate that parkin binds the native form of α-synuclein, which is the most abundant form of α-synuclein in the brain. Does parkin also interact with the native form of α-synuclein? Our own work suggests that parkin does interact with α-synuclein, because we are able to immunoprecipitate the two proteins together, however it might be that the interaction is weaker than for parkin and aSp22 (11).

Another more important question is whether parkin ubiquitinates the α-synuclein associated with Lewy bodies. This question has not yet been answered, but Shimura, Schlossmacher and colleagues report that they are unable to observe ubiquitination of α-synuclein in vitro. The apparent inability of parkin to ubiquitinate α-synuclein might be real, or might occur because the experimental conditions do not adequately mimic the conditions seen in the brains of patients with PD. It is not actually known yet whether α-synuclein in Lewy bodies is actually ubiquitinated. There are many other proteins associated with Lewy bodies that can be ubiquitinated and could account for the presence of ubiquitin in Lewy bodies. These proteins include parkin and synphilin. Whether the α-synuclein present in Lewy bodies is ubiquitinated can best be addressed by mass spectrometry, which is in progress.

These two papers demonstrate some important themes running through work in PD. First is the interest in parkin substrates. Dawson and colleagues were the first to identify a parkin substrate, termed CDCrel1 (6). Now we can add Pael-R and aSp22 as other parkin substrates. It is very likely that the upcoming year will lead to the identification of yet more substrates. The second theme is the value of ARJP brains, which are an in vivo knockout model of parkin function. Observation of elevated levels of candidate parkin substrates in ARJP brains represents an important element of proof indicating that the putative interaction is physiologically relevant. A final theme is the hypothesis that identifying proteins that bind parkin will help elucidate the mechanism of degeneration of dopaminergic neurons in PD. The upcoming research is likely to yield a large number of candidate parkin binding proteins whose importance in the pathophysiology of PD will only be known after they are tested in animal models. Of course, the final goal is to use this information to design therapies that can help people, by preventing the progression of PD.

References:

1. Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., and Shimizu, N., Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392, 605 (1998); Abstract. Return to text

2. Shimura, H., Hattori, N., Kubo, S., Yoshikawa, M., Kitada, T., Matsumine, H., Asakawa, S., Minoshima, S., Yamamura, Y., Shimizu, N., and Mizuno, Y., Immunohistochemical and subcellular localization of Parkin protein: Absence of protein in autosomal recessive juvenile Parkinsonism patients. Ann. Neurol., 45, 668 (1999); Abstract. Return to text

3. Abbas, N., Lücking, C., Ricard, S., Dürr, A., Bonifati, V., De Michele, G., Bouley, S., Vaughan, J., Gasser, T., Marconi, R., Broussolle, E., Brefel-Courbon, C., Harhangi, B., Oostra, B., Fabrizio, E., Böhme, G., Pradier, L., Wood, N., Filla, A., Meco, G., Denefle, P., Agid, Y., and Brice, A. A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Hum. Mol. Gen., 8, 567 (1999); Abstract. Return to text

4. Choi, P., Ostrerova-Golts, N., Sparkman, D., Cochran, E., Lee, J., and Wolozin, B., Parkin is metabolized by the ubiquitin/proteosomal system. NeuroReport, 11, 2635 (2000); Abstract. Return to text

5. Shimura, H., Hattori, N., Kubo, S., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., and Suzuki, T., Familial parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet, 25, 302 (2000); Abstract. Return to text

6. Zhang, Y., Gao, J., Chung, K. K., Huang, H., Dawson, V. L., and Dawson, T. M., Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A, 97, 13354 (2000); Abstract. Return to text

7. Ferrell, K., Wilkinson, C. R., Dubiel, W., and Gordon, C., Regulatory subunit interactions of the 26S proteasome, a complex problem. Trends Biochem Sci, 25, 83 (2000); Abstract. Return to text

8. Muller, S., Hoege, C., Pyrowolakis, G., and Jentsch, S., SUMO, ubiquitin's mysterious cousin. Nat Rev Mol Cell Biol. 2, 202 (2001); Abstract. Return to text

9. Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y., and Takahashi, Y., An Unfolded Putative Transmembrane Polypeptide, Which Can Lead to Endoplasmic Reticulum Stress, is a Substrate of Parkin. Cell, 105, 891 (2001); Abstract. Return to text

10. Shimura, H., Schlossmacher, M., Hattori, N., Frosch, M., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K., and Selkoe, D., Ubiquitination of a New Form of Synuclein by Parkin from Human Brain: Implications for Parkinson's Disease. Science (2001); Abstract. Return to text

11. Choi, P., Golts, N., Snyder, H., Petrucelli, L., Chong, M., Hardy, J., Sparkman, D., Cochran, E., Lee, J., and Wolozin, B., Co-association of parkin and α-synuclein. (submitted) (2001); No abstract available. Return to text

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  1. Three principal issues arise from the literature reviewed by Dr. Wolozin and his comments: (1) an evolving concept that previously separated forms of parkinsonism actually present heterogeneity of one and the same Parkinson's disease (PD) syndrome; (2) the role parkin - as a neural ubiquitin ligase - plays in the prevention of dopaminergic neurodegeneration in normal brain and in Lewy body inclusion formation during the pathogenesis of PD; and (3) the mechanism by which parkin identifies substrates that are destined to be degraded via the proteasomal pathway.

    (1) Common Parkinson's disease syndrome? Research on the genotype of parkin vis a vis the phenotype of PD has clearly demonstrated that the strict separation of familial versus sporadic, and of young onset versus late onset PD, is a concept of the past. Ujike et al. (in No To Shinkei, 1999) and the landmark paper of Lücking et al. (in NEJM, 2000) clearly identified several cases with clinically "idiopathic" PD, i.e., no family history and no known consanguinity, that were caused by deletions in the parkin-gene in an autosomal recessive manner. Likewise several studies since then have confirmed these data and demonstrated isolated cases of late onset PD linked to parkin. Thus, we should probably from here on avoid the term "autosomal recessive juvenile parkinsonism" but rather refer to these parkin-linked cases as "heritable forms of PD". As such, they clearly comprise both sporadic and inherited subtypes with various ages of disease onset, and seem to account for approximately 50 per cent of all identifiable forms of autosomal recessive PD. This convergence of genotypes and phenotypes is reminiscent of several other polygenic syndromes, e.g., Alzheimer's disease or hyperlipidaemia.

    (2) Complete versus partial loss of parkin's function ?Recently published research by Farrer et al (Annals of Neurol., 2001) represented another significant shift in PD dogmas. Previous reports indeed suggested that parkin-linked PD cases are devoid of the pathognomonic Lewy body (LB) inclusions that contain ubiquitin and alpha-synuclein (aS). However, Farrer and colleagues identified an individual who was a compound heterozygote at the parkin locus that carried LB in brainstem neurons. The unifying hypothesis we proposed is that the presence of residual parkin function (such as in Farrer's index patient 'Pw3') facilitates LB formation but is ultimately inefficient in the prevention of neurodegeneration. In contrast, loss of all parkin protein [and thus function - as was the case in the majority of the previously published LB-negative individuals that carried large parkin deletion mutations (Shimura et al., Science 2001 and references therein)] prevents the formation of LB inclusions (Schlossmacher et al., submitted). Such facilitation of insoluble inclusion formation by a neural ubiquitin ligase, E6-AP, has been demonstrated in an in vivo mouse model by Cummings et al. (Neuron, 2000). Furthermore, a partial loss of function (versus complete loss of function) of disease-linked proteins, e.g., dystrophin, has been identified as a key modulator of the resultant neurological phenotype, e.g. Becker versus Duchenne type of muscular dystrophy.

    (3) Specific signal for substrate recognition by neural parkin ?
    As a rule of thumb, RING-dependent E3 ubiquitin ligases confer specificity for the substrates they recognize, bind and ubiquitinate by virtue of a distinct signal of their target proteins. Such is the case for c-cbl that facilitates degradation of phosphorylated membrane receptors to turn off important cellular signaling events (two papers by H. Band et al., J. Biol. Chem., 2000) or for the VHL E3 ligase complex that appears specific for the hydroxylation of a single proline residue (M. Ivan et al. and P.Jaakola et al., Science 2001). It will be important to determine whether the O-linked glycosylation of alpha-synuclein, which we recently identified in human brain (Shimura et al., 2001), serves as a shared posttranslational signal for proteins that are destined to be degraded via parkin's E3 ubiquitin ligase activity. Such insight may help to better understand the pathogenesis of the PD syndrome.

References

Webinar Citations

  1. Picking up the Pieces of Parkin

News Citations

  1. Parkin and α-synuclein Linked Through Synphilin-1
  2. New Substrate for Parkin Links Disease to ER Stress
  3. Modeling Polyglutamine Diseases in Yeast Provides Support for Histone Deacetylase Connection
  4. Drugs Slow Neurodegeneration in Fly Model of Huntington's
  5. Huntingtin Regulates BDNF

Other Citations

  1. Benjamin Wolozin

External Citations

  1. http://www.proteasome.com/publications/Ferrell/diagram1.htm
  2. Abstract
  3. Abstract
  4. Abstract
  5. Abstract
  6. Abstract
  7. Abstract
  8. Abstract
  9. Abstract
  10. Abstract
  11. Abstract
  12. Zang et al. 2000
  13. Farrer et al., 2001
  14. Gai et al., 2000
  15. Trojanowski et al, 1998
  16. Satoh & Kuroda, 1999
  17. Wang et al., 1999

Further Reading

Papers

  1. . A genome-wide functional assay of signal transduction in living mammalian cells. Nat Biotechnol. 1998 Dec;16(13):1329-33. PubMed.