John Q. Trojanowski Mark P. Mattson		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 proteins.
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. Discussion Questions: 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?

View Transcript of Live Discussion — Posted 26 August 2006

Background Text

By John Q. Trojanowski, University of Pennsylvania School of Medicine, Philadelphia, and Mark P. Mattson, National Institute on Aging, Baltimore, MD.

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).

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.

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.

Acknowledgements

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: trojanow@mail.med.upenn.edu

Abnornal Protein-Protein Interactions: Mechanisms of Disease in Diverse Neurodegenerative Disorders

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.

References

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	Comments on Live Discussion
	Comment by:  Alexei R. Koudinov
	Submitted 26 August 2006  |  Permalink	Posted 26 August 2006
	Beware the Simplification in Defining Research Agenda and Major commonality for Neurodegenerative Diseases I read with interest the background text by Trojanowski and Mattson. While the authors suggest to discuss a legitimate question, the discussion agenda implies a major role for different types of amyloidoses in a number of neurodegenerative diseases. Such a view was proposed and discussed earlier (1,2). No question, however, is raised to address normal function of these proteins, and a reason for a pathological change in their neurobiochemistry, leading to oligomers and amyloid fibrils. As stated in the preface, an overlap of AD-like dementing disorders with tauopathies "are not fine points of pathological diagnosis. Rather, they imply a shared, if poorly understood, mechanism of protein aggregation". The proteins named amyloid in this discussion (particularly amyloid beta and tau, for bibliography details please see 3,4) normally represent essential physiological elements of the brain/neural/neuron self maintenance, function, plasticity....  Read more Beware the Simplification in Defining Research Agenda and Major commonality for Neurodegenerative Diseases I read with interest the background text by Trojanowski and Mattson. While the authors suggest to discuss a legitimate question, the discussion agenda implies a major role for different types of amyloidoses in a number of neurodegenerative diseases. Such a view was proposed and discussed earlier (1,2). No question, however, is raised to address normal function of these proteins, and a reason for a pathological change in their neurobiochemistry, leading to oligomers and amyloid fibrils. As stated in the preface, an overlap of AD-like dementing disorders with tauopathies "are not fine points of pathological diagnosis. Rather, they imply a shared, if poorly understood, mechanism of protein aggregation". The proteins named amyloid in this discussion (particularly amyloid beta and tau, for bibliography details please see 3,4) normally represent essential physiological elements of the brain/neural/neuron self maintenance, function, plasticity. When brain function fails due to one or another primary cause, the above proteins (and surely many others) react in an organized compensatory way to fix the function, although the proportion of the involvement and the particular compensatory reaction target could be different for different proteins and for different brain neurotransmitter systems involved. We believe that in case of Alzheimer's disease (including familiar cases), Down’s syndrome, inclusion-body myositis, the unique primary cause of neurodegeneration is a failure of neural cholesterol dynamics (5,6,7). In summary, one should be cautious in setting the 'amyloid' as major research and therapeutic agenda for proteins implicated in different neurodegenerative diseases, and defining it as "major commonality." References: 1. Williams A. Defining neurodegenerative diseases. BMJ 324, 1465 (22 June 2002). Full Text. 2. Koudinov AR, Koudinova NV Beware the simplification in defining neurodegenerative diseases. BMJ (24 June 2002). Full Text. 3. Koudinov AR, Koudinova NV. Brain cholesterol pathology is the cause of Alzheimer's disease. (19 August 2002). ARF Hypothesis. 4. Koudinov AR, Koudinova NV. Amyloid beta protein restores hippocampal long term potentiation: a central role for cholesterol? An update on "Brain cholesterol pathology is the cause of Alzheimer's disease." ARF Hypothesis (22 September 2003). ARF Hypothesis. 5. Koudinov A, Koudinova NV, Beisiegel U. Cholesterol disbalance at neuromuscular junctions and CNS synapses: a unifying cause of degeneration. BMJ (26 February 2002) FullText. 6. Koudinova NV, Koudinov AR. APP and amyloid beta protein are integrated sensor-effector system for neural cholesterol and membrane dynamics regulation. 33rd SFN Annual Meeting. Program No.23.8 (8-12 November 2003). Abstract. 7. The multifarious interactions of cholesterol, lipids, amyloid beta and TAU in the etiology of neurodegeneration. 3rd International Congress on Vascular Dementia, Prague, Czech Republic (25 October 2003). Session Titles and Abstracts. View all comments by Alexei R. Koudinov

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