John Q. Trojanowski and Mark P. Mattson discussed the major commonality
between many neurodegenerative diseases. Otherwise vastly different
conditions that run the gamut from Alzheimer's, Parkinson's, Huntington's,
ALS, to prion disorders, tauopathies and other triplet-repeat and synuclein
diseases all have in common that protein-protein interactions mysteriously
go awry in such a way that the affected person's brain becomes littered with
filamentous, and later more solid, deposits of these formerly normal
Many of these diseases feature a confusing overlap of multiple pathologies.
Examples are tangles, plaques, plus Lewy bodies seen in subtypes of AD and
elderly people with Down's Syndrome, or Lewy bodies plus amyloid plaques in
advanced PD. In fact, whole disease categories (AD-like dementing disorders)
overlap significantly with others (tauopathies) in terms of their
pathological signature. These are not fine points of pathological diagnosis.
Rather, they imply a shared, if poorly understood, mechanism of protein
aggregation. Another telltale commonality is that mutations cause the
affected protein to aggregate in familial cases of a given disease, but the
normal version of that same protein aggregates in sporadic cases. Can one
offending protein "draw" others into a common process of misfolding,
fibrillization, synaptic toxicity, and deposition? And how can understanding
this mechanism inform drug discovery?"—Gabrielle Strobel
John Q. Trojanowski and Mark P. Mattson led this live discussion on 22 October 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
1. How common are double and triple neurodegenerative brain amyloidoses?
2. What mechanisms underlie the convergence of more than one brain amyloid in many neurodegenerative diseases?
3. Will therapies directed at one amyloid affect the burden of the other amyloids and ameliorate behavioral deficits caused by each?
4. Are the amyloids detected as Lewy bodies (LBs), senile plaques (SP)s and neurofibrillary tangles (NFTs) in AD or other diseases really just the tip of the proverbial iceberg, below which there is a sea of insoluble oligomers and protofibrils that are invisible microscopically but can be detected biochemically? Do these products play a role in neurodegeneration?
5. Intracellular (NFTs, LBs) versus extracellular (SPs) amyloids: What's the difference in how they cause neurodegeneration?
6. How do protein aggregates modify synaptic function? Which synaptic signaling pathways might they compromise?
7. Can we modify the protein aggregation process by activating or inhibiting specific signal transduction pathways? If so, what might be key pathways to target for therapeutic intervention?
Participants: Gabrielle Strobel, Alzheimer Research Forum; Pete Nelson, University of Pennsylvania, Philadelphia; Davi Bock, University of Vermont; Marcos Marques, University of Cincinnati, Ohio; Paul Chabun, Elder Health, White Rock, Vancouver, British Colombia, Canada; Mikolaj Pawlak, Department of Neurology, University of Medical Science, Poznan, Poland; Alexei Koudinov, Russian Academy of Medical Sciences, Journal Neurobiology of Lipids; Edward Zamrini, University of Alabama, Birmingham; Diego Forero, National University of Colombia; Angela Biggs, Colorado; Bianca van Broeck, University of Antwerp, Belgium; Mark Mattson, National Institute on Aging, Baltimore, Maryland; John Trojanowski, University of Pennsylvania, Philadelphia.
Note: The transcript has been edited for clarity and accuracy.
Allow me to welcome everyone to discuss this fascinating topic. I am Gabrielle Strobel, managing editor of the Forum and pleased to moderate.
John Q. Trojanowski
Well, I will try to get things going by asking a question, which is: Do folks think that we underestimate the burden of misfolded proteins in neurodegenerative diseases with inclusions by relying too much on microscopy, since much of the abnormal protein accumulations may be in the form of oligomers that are not evident by microscopy, but could be detected biochemically?
One issue I am interested in is why dopaminergic neurons seem exquisitely sensitive to overload of the proteasome. The emerging findings suggest that simply increasing levels of wild-type synuclein is sufficient to cause PD. It seems as though the proteasome of dopaminergic neurons is sitting on the edge of a cliff with regards to the amount of ubiquitinated synuclein it can handle.
John Q. Trojanowski
In response to Mark, do we really know that dopaminergic neurons are so much more sensitive than other neurons to the accumulation of misfolded proteins?
We need some way of "titrating" abnormal protein accumulations and then monitoring the consequences with regards to various endpoints of interest—in my case, calcium regulation and oxidative stress.
Can I put a question out to everyone, especially John and Mark: How common are double and triple neurodegenerative brain amyloidoses? Do you have a sense of that?
John Q. Trojanowski
As we look in greater detail, especially with biochemistry allowing formic acid insolubility to be a surrogate for what is likely to be an amyloid fibril-containing protein pool, I think double and triple brain amyloidoses may be the rule rather than the exception.
Fascinating, John. So standard examination of pathological samples simply tended to overlook "other" amyloids? Certainly Kurt Jellinger has long pointed to overlapping pathologies among dementias, right?
John Q. Trojanowski
Using more traditional morphological criteria, AD is the most common triple brain amyloidosis, since there is Aβ plaque amyloid and tau tangle amyloid in all cases, and over 50 percent also have α-synuclein Lewy body amyloid.
Hello, everyone. But till now, people rarely called tau changes in AD "amyloid," right, John?
John Q. Trojanowski
Terminology has varied but there is consensus now, I think, that tangles, plaques, Lewy bodies, and other fibrillar deposits are all amyloids formed by different building-block proteins.
In biochemical/biophysical terms (β-pleated secondary structure, etc.), does tau chemistry in AD fit the amyloidosis definition? Literature avoided such definitions in the past, am I right?
John Q. Trojanowski
If you look at recent work from Goedert and Crowther in PNAS, you will find their paper with elegant data proving that tau fibrils are amyloids, and the same has been reported by many labs for α-synuclein fibrils.
What could be the mechanisms underlying the convergence of more than one brain amyloid in many neurodegenerative diseases?
John Q. Trojanowski
In mutation-bearing people, it is a mutation, but in sporadic disease it is less clear what the causes of protein misfolding and amyloidosis are.
The mechanisms are likely multifactorial. For example, oxidative stress can promote abnormal folding of proteins and protein aggregation. Overload of the proteasome seems important, and, of course, the data from studies of disease-causing mutations have provided important clues—overproduction of the long form of Aβ in AD, impaired ubiquitin-mediated proteolysis of synuclein in PD, etc. As aging is the major risk factor for the "double and triple amyloidoses," a focus should be on the age-related molecular changes.
John Q. Trojanowski
I agree with Mark on possible mechanisms in sporadic and possibly familial neurodegenerative diseases with brain amyloid deposition.
Mark, you are interested in effects of diet on aging and neurodegeneration. Do you have data on links between dietary compounds and protein misfolding/aggregation?
Gabrielle, not yet. However, Tuck Finch has recently shown that Aβ deposition is decreased in APP mutant mice on a reduced calorie diet. We have found that dietary restriction upregulates protein chaperones in neurons, which would be expected to enhance their ability to deal with damaged and abnormal proteins such as Aβ, tau, and synuclein. We will be testing the latter hypothesis in the coming months/years.
Do we know 1) if/how much any of the novel, in-vivo amyloid markers detect intracellular vs. extracellular amyloid/fibrillar deposits and 2) the relative strength of detection of one type vs. another?
I also wonder if this is another way to look at oxidative stress. I am often puzzled because it seems so obviously to spur neurodegeneration, but specific in-vivo links to, say, AD pathogenesis, are less clear to me.
John Q. Trojanowski
Oxidation could alter protein conformation leading to misfolding, and if sufficient amounts of the misfolded protein accumulate, amyloidosis could ensue. Indeed, folks like Chris Dobson might say, give me any protein and tell me how much you want converted into β-pleated sheet-containing fibrils and I can deliver them to you under the right, in-vitro conditions.
Mark, looking the other way around, how would protein misfolding, particularly amyloidosis, affect neuronal metabolism?
Marcos, we know that protein misfolding can affect neuronal metabolism, but the mechanisms are in most cases unclear. Prion proteins are good examples. Of course, patients with AD and PD have impaired cellular energy metabolism, but that this is the direct result of protein misfolding has certainly not been established.
John Q. Trojanowski
Misfolded proteins may acquire a toxic function and have deleterious consequences thereby, or by accumulating in cells, they could pull down other proteins that are taken out of action, like the misfolded protein, leading to several losses of function due to the "sidelining" of the proteins in "garbage heaps" inside cells.
Mark and Gabrielle, regarding the above point on oxidative stress, I think it is very important to look at proteins (that we call amyloid here today) as normal functional elements of brain chemistry, as I pointed out in my (prediscussion comment). Similarly, oxidative stress may well serve to modulate synaptic function and plasticity. This was proposed in several papers (see Kamsler and Segal., 2003 and Berezov et al., 2003). If so, all elements should be considered as one complex mechanism that we should attempt to understand.
John Q. Trojanowski
Again, I concur with Mark that factors which upregulate chaperones could protect cells from the toxicity associated with accumulations of misfolded proteins, be this amyloidosis or some other form of toxicity.
Regarding the relation between diet and AD, isn't it so that we are observing end results of diet applied for years and that's why it is difficult to observe a relationship between diet and disease progression in real time?
Mark and John, all, there is a paper in Science this Friday about C. elegans living six times their normal life span, and being highly active (see related news story). They have a few mutations, mostly in insulin-related signaling. Does this suggest anything as to which signaling pathways should be checked for changes in human aging and neurodegeneration (although I am not aware of links between aging pathways and protein aggregation)?
John Q. Trojanowski
I am not certain which of the signaling pathways in the worms would be worth pursuing in human neurodegenerative diseases, but that is a good thought to consider.
Gabrielle, there is another recent paper (not in Science) which shows that a particular profile of lipoproteins is associated with extreme longevity. This may well be of importance in terms of a role for lipids and cholesterol in AD (see our ARF hypothesis page) and LP signaling (see Herz and Strickland, 2001).
Gabrielle, mutations in the insulin signaling pathway increase life span and stress resistance in C. elegans. Apparently, the mutations relieve suppression of a forkhead transcription factor, resulting in increased expression of antioxidant enzymes and perhaps proteins involved in preventing protein damage and/or removing damaged/misfolded proteins.
Fascinating, Mark. Gene expression studies of aging humans are coming along, and consistently seem to show differences (downregulation) of genes involved in stress response, DNA repair etc.... All this calls for more work on chaperones. As far as I know, chaperone genes tend not to come up much in screens for genes involved in neurodegeneration in, say, Drosophila or worms. How could one study their role in these multiple amyloidoses better?
One question seems to be: Which are chickens and which are eggs?
Pete Nelson's question is very important. What is the primary mechanism in the amyloidosis? It may be only the visible consequences of other underlying pathogenic pathways.
John Q. Trojanowski
As to the chicken and egg question, I think things may go in either direction, since if one is born with a mutation in tau, this determines subsequent formation of tau amyloid, so you consider tau amyloid the egg because it can come first, i.e., disease begins at conception. But in sporadic disease, there may be many chickens laying eggs that break, damaging tau and precipitating aggregation to form tangles. Sorry to overdo the chicken/egg analogy, but that was how the question was framed.
Sorry to use a riddle for a metaphor!
Both riddles and metaphors are fair game, Pete!
Understanding the normal functions of synuclein, tau, and Aβ is important. It is of considerable interest, in this regard, that synuclein, tau, and APP are axonal proteins. Their normal functions in axons and presynaptic terminals may provide important clues as to the earliest events in disease pathogenesis, as well as to how the abnormal protein aggregates arise.
Does this point to axonal transport, then, as one possible unifying theme of what goes awry?
Yep, axonal transport and synaptic vesicle recycling might be adversely affected early on in the course of the disease process.
John Q. Trojanowski
This is a good point on the possibility that in all of these diseases there could be a disruption of transport because the disease proteins bind or perturb motor proteins, disassemble microtubules, or physically block traffic when large amyloid accumulations formed by tau or α-synuclein develop in axons as dystrophic neurites or Lewy neurites.
The topics pointed out by Dr. Koudinov are also very important. We may try to understand the possible pathogenic pathways in amyloidosis, taking into account that these proteins are key regulators of neural function, not only "bad" amyloids.
To Diego and Pete on primary factor: I believe that I attempted to address this question through the prism of functional role for "amyloid" proteins in normal synaptic function/plasticity (see comment on the ARF live discussion). For example, with regard to oxidative stress and normal/pathological amyloid biochemistry, an interesting sequence of events is proposed by A. Kontush (see abstract), which is that Aβ initially serves as an antioxidant, but its increased production as antioxidant leads to the peptide-aggregated pro-oxidative form.
Did anybody look at amyloid animal models for changes in parameters like diet and exercise as a means to reverse the neuronal metabolism imbalance, and at the molecular level, is it possible to determine, then, how amyloid affects neuronal metabolism?
John, as an esteemed pathologist, what do you think of Larry Goldstein's argument that many of the swellings one commonly sees in neurodegenerative diseases are axonal blockages that induce, not accompany, damage?
John Q. Trojanowski
Mark, what has become of "synaptosis"? This was the concept that the disease protein may lead to programmed death of processes, and I think you and others proposed this possibility a while ago.
John, do you mean a local apoptosis program in dendrites and terminals?
John Q. Trojanowski
Gabrielle, as you may recall from my recent commentary on the papers from the Brady and Goldstein labs, I was pleased to see the concept of axonal transport-induced degeneration extended from AD, where it has been around for over 10 years, to other disorders such as polyQ diseases, and I think it plausible that impairments in axonal transport could be drivers for degeneration in multiple aging-related neurodegenerative disorders.
The evidence that activation of apoptotic cascades occurs in synapses, axons, and dendrites is quite strong, and it is clear that these cascades can propagate to the cell body, culminating in death. It is also becoming evident that apoptotic cascades can have local effects on synaptic function and structural remodeling in the absence of cell death. The possible links between the amyloid proteins under consideration here and apoptotic processes remain to be determined, although we do know that Aβ can induce "synaptic apoptosis," at least in cell culture and synaptosome preparations.
Here's a reference about the concept of synaptic apoptosis developed by Mattson et al., 1998
John Q. Trojanowski
One would assume a progression from oligomers, to protofibrils, to fully formed amyloid fibrils based on in-vitro studies, and this process could unfold anywhere in a cell. Indeed, we have shown by stereology (Mitchell et al., 2000) that only five percent of the area occupied by abnormal tau immunoreactivity in AD is in tangles, while 95 percent is in the dystrophic processes, which means that it is surprising that tangles correlate with dementia because most of the tau pathology is in processes which are not normally counted in correlative studies.
Charlie Glabe reported an antibody that appears to recognize mid-size oligomers of a number of fibrillogenic proteins (see related news story). Would that be a useful tool to study the synergy you propose between different aggregation-prone proteins? Does the antibody stain in-vivo sections of different disease brains?
I was recently reviewing literature on a functional role of Aβ/APP (with regard to a unifying role for cholesterol in synaptic degeneration), and found Askansas et al., 1992 and Torroja et al., 1999. Do the above imply that we miss a more general point while talking about a neurodegeneration commonality—a role for proteins in synaptic machinery?
John and Mark, does your thinking say anything about where along the way of aggregation the damage happens to the synapse? Oligomers? Protofibrils? Fibrils? Do you consider this question important at all?
Gabrielle, we come ourselves to the conclusion that amyloid fibrils can damage synaptic plasticity and that diffuse amyloid has no such effect. For me, the major question is what causes the change in Aβ biology. When we understand this, we will be able to reverse amyloid by affecting the primary cause.
John Q. Trojanowski
And this "synaptic apoptotic" damage could be compounded by impairments in axonal transport caused by an accumulation of insoluble tau or α-synuclein, because transport of key synaptic proteins would not occur normally, nor would trophic factors picked up at terminals be transported back to the perikaryon to sustain the viability of affected neurons.
What is the role of ubiquitin-proteasome degradation in this? It would seem to be a candidate for a shared mechanism, as it pops up in some way in all these diseases. But I see no overarching theme yet. Have I missed it? One interesting lead might be that Mike Ehlers studies proteasome degradation in dendrites as a mechanism involved in activity-dependent turnover of postsynaptic proteins.
Ubiquitin-mediated protein degradation seems to be at the heart of the problem in Parkinson's disease as parkin is an E3 ligase and synuclein a substrate. In the case of Alzheimer's, Aβ, and tau, the importance of the proteasome is less clear.
John Q. Trojanowski
Amyloidosis is a product of several mechanisms, including the oversupply of substrates for amyloidogenesis and the diminished clearance of substrates allowing accumulations that precipitate into amyloid fibrils under the appropriate in-vitro conditions.
John, regarding distribution of abnormal tau: Perhaps the tangles are more inflammatory than the dystrophic processes. One oft-neglected clue is that APP has an iron response element (Rogers et al., 2002) and an IL-1 element (Rogers et al., 1999) in its 5' UTR. I wonder if a unifying feature of these amyloidogenic proteins is that they are upregulated by inflammatory processes, and so when they themselves instigate an inflammatory process (due to stochastic misfolding which increases with age, for example), a positive feedback loop is initiated?
John Q. Trojanowski
In response to your query, oxidate/nitrative stress could be another chicken/egg phenomenon, in that it may increase with the accumulation of misfolded proteins, or if increased for other reasons, it could contribute to amyloidogenesis.
Diego's reference reminded me of another major observation: that PHF-like tau change occurs normally during the short ontogenic period of intense (and membrane cholesterol-demanding) nerve growth (see Koudinov and Koudinova 2003). Can we call this condition amyloidosis? Nature developed it to serve neural/synaptic function. In the disease, therefore, this machinery may serve to compensate synaptic failure. Can it be called a pathological event? Or compensation would be a better definition. This will be available soon as a peer-reviewed publication.
The developmental changes in tau involve hyperphosphorylation and not aggregation of tau into filaments. It is clear that hyperphosphorylation of tau, pre se, is not harmful to neurons, as it occurs normally in development. This is important, as it tends to dissociate phosphorylation from the pathogenic process in AD and related tauopathies.
Mark, there is certainly a borderline between natural normal compensation and a disease-locked condition. Therefore, one should better and strictly define new amyloid proteins, so there will be no confusion (see the beginning of this discussion).
John Q. Trojanowski
Mark, hyperphosphorylation or any phosphorylation of tau is not needed for in-vitro tau amyloid fibril formation, and the tau gene mutations argue that abnormal tau phosphorylation is not the most upstream event in familial tauopathies. However, since the increasing phosphorylation decreases microtubule binding, the excess phosphorylation of tau would disengage it from microtubules and this will destabilize microtubules to impair axonal transport, while leading to pools of unbound tau that could reach concentration thresholds which result in tau fibrillization.
If you can't stop amyloidogenesis, can you at least slow it down by limiting substrates? If yes, then how?
John Q. Trojanowski
Yes, and that is the purpose of β-secretase inhibitor therapies that are intended to reduce the levels of Aβ peptides, which are the substrates for amyloid fibril formation. Alternatively, vaccine therapies, and gene therapy to increase expression of neprylisin, would be other avenues of therapeutic intervention to reduce Aβ plaques in AD.
I see. Thanks. How about physiological processes influencing this pathway?
John and Mark, can you tell us more about these aggregation-busting compounds you mention in the article? Sorry for the barrage of questions—this is so interesting!
John, with regard to Aβ-lowering therapies, one should be sure that no normal pathway is affected—a subject deserving study.
The new drug Velcade is a proteasome inhibitor and now in trials for prostate cancer. I wonder what would happen if it got into the brain of people with breaks in the BBB?
Yes, if the Velcade gets into the brain, it would likely be bad for neurons. Of course, if you have life-threatening cancer, you might not be too worried about increased risk of neurodegenerative disorders.
Mark, I totally agree. Indolent prostate cancer, though, is a different beast from active multiple myeloma....
Just to rock the boat at the end of the hour: I find the notion of a shared mechanism the least convincing in AD because of the spatial separation between tangles and plaques. Do you think that Aβ misfolding and fibrillization begins intraneuronally, where perhaps its aggregation could interact with tau and α-synuclein?
My own $0.02, vis-à-vis Gabrielle's observation: Neuritic plaques seem to me to represent an important nidus of pathology, as (extracellular) amyloid plaques are directly apposed to (intracellular) neurofibrillary pathology, and degenerating neurites. Somehow, one is very directly interacting with the other!
Yes, but Pete, how can they interact "very directly" when there is a cell membrane in the middle?
The cell membranes are compromised in neuritic plaques, as shown early on by Terry, Wisniewski, and other ultrastructural microscopists.
John Q. Trojanowski
On rocking boats, I would emphasize that what we see in the way of amyloid deposits through a microscope is the tip of the iceberg, in my view, since I expect that the AD brain is awash in variable levels of Aβ, tau, and often α-synuclein oligomers, so interactions could well take place outside the field of view of a microscope.
What if accumulation was due to the neuron being in the growth mode of the axon...assuming all three—tau, synuclein, and APP—were involved in growth...and perhaps the nerve became stuck in the growth mode? Decrease the amount of substrate buildup by learning how to get the nerve out of the growth mode? Does that make sense?
Interesting point, Angela. I think that it may be the case, although now there is only indirect evidence for it.
I've been working on an idea whereby serpins stop growth and serine proteases trigger growth...and I find it suggestive that AβPP is a serine protease receptor—nexin. Then, insertion of neuroserpin stops the extension of axons, right?
Can I ask another question about drug discovery based on your hypothesis, John and Mark? Does it open new avenues to make stronger drugs than vitamin E out of the oxidative damage knowledge?
Antioxidants continue to hold therapeutic potential and many labs are working to identify novel antioxidants which easily enter the brain and scavenge radicals. It's hard to say whether they will have a major impact on the disease process, although they are likely to have some benefit with few side effects.
I have to run. Thanks so much to you, Gabrielle and ARF, and much thanks to Drs. Mattson and Trojanowski, and the others. I enjoyed the hour!
John Q. Trojanowski
To paraphrase Mae West: So many fascinating questions and hypotheses, so little time, and it is the end of the hour for me, so I will send greetings to all and thanks for the lively chat!
John, on rocking boats: Aha, thanks. I am beginning to see this majority view now, that there is this sea of different aggregating species, few of which are visible with a microscope.
I agree with John about the iceberg tip, and look forward to more great data by scientists in many related fields. Thank you to all for the discussion and to ARF for organizing/holding it.
Let me thank you all for coming and for this fascinating discussion. We clearly need to revisit this topic.
Thank you again, ARF team, congratulations!!
For John, perhaps for a later time regarding the tip of the iceberg. So, could any of the new amyloid markers detect levels of oligomers heretofore undetectable by microscopy? Bye, everyone.
One hopes PIB will, and new antibodies. So, Mark, should we go on calorie restriction in the meantime?
Gabrielle, thanks for the opportunity. John, thank you for your efforts on the special issue of the journal and this online chat. Hope to see you in New Orleans. Gabrielle, yes, it's very likely that each of our brains would benefit from smaller or less frequent meals. In addition to helping your neurons deal with damaged proteins, dietary restriction upregulates expression of neurotrophic factors, particularly BDNF. Our data suggest that BDNF mediates several beneficial effects of dietary restriction in the brain, including neuroprotection and stimulation of neurogenesis.
Bye, everyone, and please come back.
Note: This background text is an introductory article for a special issue of NeuroMolecular Medicine, posted courtesy of Humana Press.
Reference: Trojanowski, John Q.; Mattson, Mark P.
Protein Aggregation in Neurodegenerative Brain Disorders. NeuroMolecular Medicine. October 2003; Volume 4, Issue 1-2:pp 1-6.
Recognition of a common mechanistic theme shared by Alzheimer's disease (AD) and many other neurodegenerative disorders has emerged with the increasing appreciation that a large number of these disorders are characterized neuropathologically by intracellular and/or extracellular aggregates of proteinacious fibrils or amyloids (see Table below), and that these lesions are not mere markers of the disease state, but are directly implicated in progressive brain degeneration (4,7-10,12,17-19,21,22).
Thus, despite differences in the molecular composition of the filamentous lesions in neurodegenerative disorders such as AD, Parkinson's disease (PD) and related synucleinopathies, Frontotemporal Dementias (FTDs) and related tauopathies, prion disorders, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat diseases, growing evidence suggests that similar pathological mechanisms may underlie all of these disorders. Specifically, the onset and/or progression of brain degeneration in AD and other neurodegenerative disorders may be linked mechanistically to abnormal interactions between brain proteins that lead to the assembly of the disease proteins into filaments and the aggregation of these filaments within brain cells or in the extracellular space.
Sporadic and familial AD (FAD) are among the most common and well known of this group of diseases, and in AD these filamentous lesions are exemplified by intracytoplasmic neurofibrillary tangles (NFTs) as well as extracellular amyloid or senile (SPs) or amyloid plaques (4,8-10,17-19,21). Although filamentous lesions formed by distinct proteins are recognized as diagnostic hallmarks of specific disorders, sporadic AD and FAD illustrate some of the complex and poorly understood overlap among these neurodegenerative diseases. For example, the heterogeneous dementing disorders classified as AD overlap with a large group of distinct neurodegenerative disorders that are collectively known as tauopathies, and tauopathies are characterized by prominent tau-rich tangle pathology throughout the brain (12).
However, AD also overlaps with another diverse group of disorders known as synucleinopathies that are characterized by filamentous a-synuclein brain pathology (22). Thus, while the diagnostic hallmarks of AD are numerous SPs composed of A fibrils and intraneuronal NFTs form by aggregated tau filaments, NFTs are similar to the filamentous tau inclusions characteristic of neurodegenerative tauopathies, many of which do not show other diagnostic disease specific lesions. Notably, tau gene mutations have been shown to cause familial FTD and parkinsonism linked to chromosome 17 (FTDP-17) in many kindreds (12). Moreover, Lewy bodies (LBs), the hallmark intracytoplasmic neuronal inclusions of PD, also occur in the most common subtype of AD known as the LB variant of AD (LBVAD), and numerous cortical LBs are the defining brain lesions of dementia with LBs (DLB), which is similar to AD clinically, but distinct from AD pathologically (21,22).
Further, a-synuclein gene mutations cause familial PD in rare kindreds, and these mutations may be pathogenic by altering the properties of a-synuclein thereby promoting the formation of a-synuclein filaments that aggregate into LBs (22). However, it is now known that FAD mutations and trisomy 21 lead to abundant accumulations of LBs and Lewy neurites or dystrophic processes containing protein aggregates composed of a-synuclein filaments in the brains of most FAD and elderly Down's syndrome (DS) patients, respectively. However, it is unclear how these genetic abnormalities promote the formation of LBs from wild type a-synuclein proteins encoded by a normal gene. Nonetheless, the accumulation of a-synuclein into filamentous inclusions appears to play a mechanistic role in the pathogenesis of a number of progressive neurological disorders including PD, DLB, DS, FAD, LBVAD, sporadic AD, multiple system atrophy, and other synucleinopathies while amyloid deposits formed by other subunit proteins are characteristic of prion disorders, ALS and trinucleotide repeat diseases (21,22).
Thus, many neurodegenerative diseases (but not all of the disorders listed in the Table or reviewed in this Special Issue) share an enigmatic symmetry, i.e. missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild type brain protein in a sporadic variants of the disease. Moreover, AD is one of the more striking examples of a "triple brain amlyloidosis", i.e. a neurodegenerative disorder wherein at least three different building block proteins (tau, a-synuclein) or peptide fragments (Ab) of a larger Ab precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons.
However, there are examples of other triple brain amyloidoses such as DS and Mariana Island dementia or Guam Parkinson's-dementia Complex (Guam PDC) that also show evidence of accumulations of amyloid deposits formed by tau, a-synuclein and Ab, and there is increasing recognition that tau or a-synuclein intraneuronal inclusions may converge with extracellular deposits of Ab in "double brain amyloidoses" as exemplified by the abundant tau inclusions in a member of the Contursi kindred with familial PD, the presence of LBs or NFTs in patients with prion disease, the co-occurrence of PD with abundant Ab deposits and dementia or LBs with progressive supranuclear palsy in some patients.
Accordingly, clarification of this enigmatic symmetry in any one of these disorders is likely to have a profound impact on understanding the mechanisms that underlie other of these diseases as well as on efforts to develop novel therapies to treat them. For this reason, this Special Issue of NeuroMolecular Medicine focuses on shared underlying mechanisms common to these and other disorders mentioned here including the specific pathobiology of the different types of amyloid that are characteristic of each of these diseases as well as cellular mechanisms that may promote or inhibit accumulations of protein aggregates (oxidative stress, proteosome/ubiquitin systems, chaperone/heat shock protein responses, genetic mutations, etc.) with the expectation that insights into these mechanism will accelerate the pace of the successful discovery of drugs to treat these neurodegenerative brain amyloidoses (1-3,5,6,13,18,23).
Taken together, a growing number of recent advances into understanding brain amyloidosis in these disorders prompt consideration of pathogenic scenarios wherein synergistic interactions between tau, Ab and a-synuclein amyloid may occur, or the early intermediates and protofibrillar species of tau, Ab and a-synuclein mediate brain degeneration in AD (7,19). These uncertainties notwithstanding, the insights into brain amyloidosis in AD and related neurodegenerative diseases mentioned above argue that an informed and accurate view of the sequence of events leading to brain degeneration in triple and double brain amyloidoses will come with additional new data from experimental studies (e.g. in cell culture and animal model systems) that rigorously test competing hypotheses about the cascade of events leading to brain degeneration in AD and other neurodegenerative brain amyloidoses.
For example, hypothetical events that might underlie protein fibrillization and aggregate formation or the toxicity associated with misfolded proteins include increased intracellular oxidative stress coupled with a failure of normal cellular anti-oxidant mechanisms or impairments in molecular chaperones and protein re-folding mechanisms or excitotoxicity (1-7,14,15,18,19). Indeed, there may be a plethora of pathways leading to protein misfolding with the subsequent formation of toxic amyloid deposits (be they formed by tau, Ab, a-synuclein, prions, or polyglutamine tracts), and a much larger array of proteins than previously anticipated may be vulnerable to misfold or fibrillize and cause disease as a result of a variety of noxious or stressful cellular perturbations.
Nonetheless, even in the absence of a complete understanding of these processes, sufficient information is available now to embark on drug discovery efforts to develop more effective therapies for protein misfolding diseases including neurodegenerative brain amyloidoses such as AD, synucleinopathies and tauopathies (11,13,16,18-20). For example, compounds have been identified that prevent the conversion of normal proteins into abnormal conformers or variants with structural properties that predispose the pathological proteins to form potentially toxic filamentous aggregates, and it is also plausible to speculate that some of these agents may have therapeutic efficacy in more than one neurodegenerative disorder. Thus, while more profound insights into abnormal protein-protein interactions and protein misfolding from continuing research advances will coalesce in the future to clarify the earliest upstream events in neurodegenerative brain amyloidoses, it is nonetheless timely now to embark on efforts to discover new and better therapies for AD, syucleinopathies, tauopathies, prion diseases, trinucleotide repeat disorders and other devastating neurodegenerative disorders caused by abnormal filamentous aggregates.
The co-editors of this Special Issue of NeuroMolecular Medicine thank all
investigators who contributed to make it a success. The research summarized
here was supported by the National Institute on Aging of the National
Institutes of Health, the Alzheimer's Association, and the Michael J. Fox
Foundation. Visit http://www.med.upenn.edu/cndr for more information on
neurodegenerative diseases. Finally, we want to thank the families of our
patients, whose generous support made this research possible.
*Address correspondence to: firstname.lastname@example.org
Abnornal Protein-Protein Interactions: Mechanisms of Disease in Diverse Neurodegenerative Disorders
|ALS*||Spheroids/NF subunits, SOD1||Intracytoplasmic|
|NBIA 1#||LBs/ a-synuclein
|NIID||Inclusions/Expanded poly-glutamine tracts||Intranuclear|
|Prion diseases*||Amyloid plaques/Prions||Extracellular|
|Tri-nucleotide repeat diseases||Inclusions/Expanded poly-glutamine tracts||Intranuclear and Intradendritic|
This table lists hereditary and sporadic neurodegenerative disorders characterized neuropathologically by prominent filamentous lesions. Most lesions are in nuclei, cell bodies and processes of neurons and/or glia, but some are extracellular (i.e. SPs).
The abbreviations used here are: A= Amyloid-bpeptides, AD = Alzheimer's disease, ALS = Amytrophic lateral sclerosis, DLB = Dementia with Lewy bodies, DS = Down's syndrome, GCIs = Glial cytoplasmic inclusions, LBs = Lewy bodies, LBVAD = Lewy body variant of Alzheimer's disease, MSA = Multiple system atrophy, NBIA 1 = Neurodegeneration with brain iron accumulation type 1, NF = Neurofilaments, NFTs = Neurofibrillary tangles, NIID = Neuronal intranuclear inclusion disease, PD = Parkinson's disease, PHFtau = Paired helical filament tau, RBD= REM behavioral disorder, SOD1 = Superoxide dismutase 1, SPs = Senile plaques.
* Both hereditary and sporadic forms of these disorders occur.
@ Neurodegenerative diseases with prominent tau pathology are tauopathies.
# Neurodegenerative diseases with prominent synuclein pathology are synucleinopathies.
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2. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002 Feb 1;295(5556):865-8. Abstract
3. Bonini NM. Chaperoning brain degeneration. Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4():16407-11. Abstract
4. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002 Apr 4;416(6880):507-11. Abstract
5. Giasson BI, Ischiropoulos H, Lee VM, Trojanowski JQ. The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer's and Parkinson's diseases(1,2). Free Radic Biol Med. 2002 Jun 15;32(12):1264-75. Abstract
6. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science. 2000 Nov 3;290(5493):985-9. Abstract
7. Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. Abstract
8. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997 Apr ;20(4):154-9. Abstract
9. Hardy J, Allsop . Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991 Oct ;12(10):383-8. Abstract
10. Hardy J. Genetic dissection of primary neurodegenerative diseases. Biochem Soc Symp. 2001 ;:51-7. Abstract
11. Irizarry MC, Hyman BT. Alzheimer disease therapeutics. J Neuropathol Exp Neurol. 2001 Oct ;60(10):923-8. Abstract
12. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001 ;24():1121-59. Abstract
13. Loo TW, Clarke DM. Application of chemical chaperones to the rescue of folding defects. Methods Mol Biol. 2003 ;232():231-44. Abstract
14. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997 ;23(1):134-47. Abstract
15. Mattson M. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003 ;3(2):65-94. Abstract
16. Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med. 1999 Nov 25;341(22):1670-9. Abstract
17. Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci. 2002 Jan ;25(1):22-6. Abstract
18. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003 Jan ;4(1):49-60. Abstract
19. Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science. 2002 Jun 14;296(5575):1991-5. Abstract
20. Trojanowski JQ. "Emerging Alzheimer's disease therapies: focusing on the future". Neurobiol Aging. 2002 Nov-Dec ;23(6):985-90. Abstract
21. Trojanowski JQ, Lee VM. "Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann N Y Acad Sci. 2000 ;924():62-7. Abstract
22. Trojanowski JQ, Lee VM. Parkinson's disease and related alpha-synucleinopathies are brain amyloidoses. Ann N Y Acad Sci. 2003 Jun ;991():107-10. Abstract
23. Welch WJ, Gambetti P. Chaperoning brain diseases. Nature. 1998 Mar 5;392(6671):23-4. No abstract available. Abstract
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- Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121-59. PubMed.
- Loo TW, Clarke DM. Application of chemical chaperones to the rescue of folding defects. Methods Mol Biol. 2003;232:231-43. PubMed.
- Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997;23(1):134-47. PubMed.
- Mattson MP. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med. 2003;3(2):65-94. PubMed.
- Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med. 1999 Nov 25;341(22):1670-9. PubMed.
- Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists finally shake hands?. Trends Neurosci. 2002 Jan;25(1):22-6. PubMed.
- Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003 Jan;4(1):49-60. PubMed.
- Taylor JP, Hardy J, Fischbeck KH. Toxic proteins in neurodegenerative disease. Science. 2002 Jun 14;296(5575):1991-5. PubMed.
- Trojanowski JQ. "Emerging Alzheimer's disease therapies: focusing on the future". Neurobiol Aging. 2002 Nov-Dec;23(6):985-90. PubMed.
- Trojanowski JQ, Lee VM. "Fatal attractions" of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann N Y Acad Sci. 2000;924:62-7. PubMed.
- Trojanowski JQ, Lee VM. Parkinson's disease and related alpha-synucleinopathies are brain amyloidoses. Ann N Y Acad Sci. 2003 Jun;991:107-10. PubMed.
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