Sci. Aging Knowl. Environ., 13 August 2003
Vol. 2003, Issue 32, p. pe23
[DOI: 10.1126/sageke.2003.32.pe23]


Meeting Summary--Cell Biology of Parkinson's Disease and Related Neurodegenerative Disorders

John Q. Trojanowski, and Virginia M.-Y. Lee

The authors are with the Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. E-mail: trojanow{at} (J.Q.T).;2003/32/pe23

Key Words: Parkinson's disease • parkinsonism • movement disorders • neurodegenerative diseases


Parkinson's disease (PD) is the most common neurodegenerative movement disorder (see Constantino Case Study). Whereas the classic clinical-neuropathological features of PD have been well established, the mechanisms underlying brain degeneration in PD are unknown, and only partially effective symptomatic treatments for PD exist. Furthermore, there are no therapeutic interventions that prevent PD or block the progression of this relentless neurodegenerative disorder. Nonetheless, the prominent loss of dopamine in the substantia nigra, which leads to impaired normal and smooth movements (known as extrapyramidal impairments), can be corrected partially for a limited portion of the disease course by giving drugs that replace or supplement the low dopamine levels caused by the loss of neurons that produce this neurotransmitter.

Recent research has led to a better understanding of the cell biology of PD. PD and clinically related disorders are characterized by accumulations of misfolded proteins that aggregate into deposits called amyloids, which are abnormal fibrils with abundant beta-pleated sheet structure and other characteristic physicochemical properties. For example, deposits of alpha-synuclein and other proteins form intraneural aggregates called Lewy bodies (LBs), a characteristic feature of the most common form of PD (Fig. 1). Dramatic new insights into the role of alpha-synuclein in the pathobiology of PD have emerged recently (see "Dumpster Diving" and "Deadly Giveaway"), and these have led to the development of transgenic animal models that display PD-like alpha-synuclein pathologies (that is, LBs and Lewy neurites, which are axons and dendrites of nerve cells that are pathologically altered by accumulations of fibrillar alpha-synuclein deposits). At the same time, other neurodegenerative PD-like movement disorders also are beginning to be more clearly understood as a result of genetic insights into familial forms of these diseases and molecular biological advances in elucidating their underlying mechanisms. These mechanisms involve abnormalities in proteins including Parkin, the microtubule-associated protein tau, DJ-1, and ubiquitin carboxyl hydrolase. Continuing research in this direction should advance our understanding of PD and related movement disorders as well as accelerate discovery of more effective therapies for these aging-related neurodegenerative conditions.

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Fig. 1. Electron micrograph of a LB. The image shows a substantia nigra dopaminergic neuron with a LB filling the cytoplasm. The LB is formed by a starburst array of amyloid fibrils formed by alpha-synuclein and it is labeled here by antibodies that recognize alpha-synuclein. The other dark particles around the LB are neuromelanin granules. Scale bar, 2 µm.

This Perspective provides a summary of recent advances in PD-related research that were described at a meeting entitled "Cell Biology of Parkinson's Disease and Related Neurodegenerative Disorders" held in Bethesda, Maryland, in June 2003. The meeting was organized by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) and sponsored by NINDS. Creighton Phelps of NIA and Diane Murphy of NINDS were the lead organizers of this meeting.

Theme I: Clinicopathological Correlations

Clash of the Titans! Convergence of diverse amyloids in neurodegenerative diseases

One of the authors of this Perspective, John Q. Trojanowski, provided an overview of the diverse familial and sporadic neurodegenerative diseases that manifest in whole or in part by extrapyramidal signs (which reflect abnormalities in the smooth execution of voluntary movements) or parkinsonism (symptoms that are characteristic of PD, including tremors, muscle rigidity, and loss of balance). This summary emphasized the heterogeneity of these disorders (Fig. 2). Adding further complexity to current classification and understanding of these neurodegenerative parkinsonian disorders is the fact that they may be associated with more than one form of amyloid deposit in the brain and thus can be regarded as single, double, and triple brain amyloidoses. The most common subtype of Alzheimer's disease (AD) (known as the LB variant of AD) is an example of a triple amyloidosis, because there are accumulations of three different forms of amyloid in the brain: (i) LBs formed of alpha-synuclein amyloid fibrils, (ii) senile plaques formed of amyloid-{beta} (A{beta} fibrils, and (iii) neurofibrillary tangles formed by tau amyloid fibrils. Thus, it was stressed that there is an increasing need to align current nomenclature of parkinsonian disorders with the rapidly growing insights into the genetic and cell biological mechanisms that underly these disorders. Such a movement would help to promote greater diagnostic accuracy, to facilitate communications between researchers, clinicians, and patients, and to enhance the pace of research to identify more effective therapies for these diseases. For example, given the clinical similarities between the various forms of parkinsonisms, it might be more informative to base the nomenclature of movement disorders on the genetic or mechanistic basis for the etiologically distinct forms of parkinsonism.

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Fig. 2. Neurodegenerative parkinsonian disorders. Disorders can be classified as single, double, or triple brain amyloidoses. For example, if only tau amyloid deposits such as tangles are present, the disorder represents a single amyloidosis, whereas if all three types of deposits (A{beta}, tau, and LBs) are present, the disorder is a triple amyloidosis. Park 1 through 10 are the 10 genes linked to familial PD. The identity of some of these genes has been determined, and they have been shown to encode Parkin, alpha-synuclein, tau, and DJ-1, for example. The identity of other Park genes remains unknown.

New neuropathology of PD revealed by immunohistochemistry

Dennis Dickson reviewed recent advances in understanding the neuropathology of parkinsonian disorders. He emphasized that clinical parkinsonism reflects the brain regions involved. For example, the movement impairments in these disorders are caused by neurodegeneration of the brainstem and basal ganglia (especially the substantia nigra, a region of the basal ganglia important for the control of movement) (Fig. 3). In addition, he stressed that the clinical manifestations of the disease do not necessarily predict the nature of the underlying pathology or disease mechanisms. For example, LBs are formed by fibrillar aggregates of alpha-synuclein, but a host of other components may be specifically or nonspecifically trapped in LBs. Furthermore, there is increasing evidence that LB diseases have a wider distribution of alpha-synuclein fibrillar deposits than previously appreciated, as revealed recently with improved antibodies that recognize alpha-synuclein. Thus, fibrillar alpha-synuclein deposits occur in Lewy neurites throughout the neocortex and subcortical regions of the brain, as well as in glial cells. There is also widespread superficial cortical spongiosis (that is, vacuolar abnormalities in cells and the neuropil, a network of synaptic terminals, dendrites, and glial processes) in LB disease brains, which had not been appreciated earlier. Further, efforts to stage PD show that there is primarily a caudal to rostral (back to front) progression in the regions affected by alpha-synuclein pathologies, although the olfactory bulb (which is located at the base of the frontal lobes behind and above the nose) also is affected in early stages of the disease. Other points that were made include the following: (i) Observations that aggregates containing tau and alpha-synuclein colocalize in the brains of the same patients more frequently than previously suspected argue for a mechanistic interaction between the two. (ii) Alpha-synuclein pathology involving the complex of deep brain nuclei made up of basal ganglia and associated structures is a newly identified feature of dementia with LBs (DLB), PD, and PD with dementia, which is more common than initially believed. (iii) Alpha-synuclein and A{beta} pathologies converge more frequently than previously suspected, and this observation argues for a mechanistic interaction between the two. (iv) The colocalization of fibrillar deposits of alpha-synuclein, tau, and A{beta} are increasingly appreciated as common features of LB diseases.

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Fig. 3. PD brain versus normal brain. (A) A section of human midbrain from a person affected by PD. (B) A comparable section from a neurologically normal person of about the same age. In the normal ventral midbrain, there is a dark black band called the substantia nigra (arrow). In the PD brain, this band (arrow) is much paler, reflecting the degeneration and loss of pigmented cells, which is frequently evident even at a macroscopic level (from the Constantino Case Study).

Theme II: Genetics of PD and Related Disorders

The role of DJ-1 in PD

Peter Heutink reviewed events leading to the discovery of the gene (DJ-1) associated with one form of autosomal recessive PD, known as Park 7. The DJ-1 gene has eight exons (exons 1A/B are alternatively spliced) and is ubiquitously expressed as a ~1-kb transcript. Genomic rearrangements in DJ-1 have been found in a Dutch family with PD, whereas a point mutation resulting in a change in a conserved amino acid (Leu166->Pro166) in the DJ-1 protein has been found in an Italian family with PD. Ongoing studies of DJ-1 include analysis of (i) the DJ-1 gene in other PD kindreds (in which other mutations appear to have been identified); (ii) the neurodegenerative disease phenotype associated with mutations in DJ-1; (iii) the role of DJ-1 in male fertility (to understand the range of abnormalities caused by mutations in DJ-1); (iv) the function of the DJ-1 protein; (v) the role of DJ-1 in stress responses; and (vi) the role of DJ-1 in mechanisms of neurodegenerative disease. New data on DJ-1 biology were summarized, including (i) evidence that the DJ-1 protein is localized to mitochondria in cultured cells transfected with the DJ-1 gene; (ii) the finding that newly generated antibodies recognize a 20-kD, monomeric protein, and that wild-type (WT) DJ-1 exists as dimers in cells, whereas the Leu166->Pro166 mutant form is more commonly found in higher molecular weight species, suggesting that it aggregates more readily; and (iii) the discovery that WT DJ-1 has a half-life of greater than 24 hours, whereas the Leu166->Pro166 mutant form has a half-life of less than 3 hours. Speculative suggestions are that DJ-1 plays a role in redox mechanisms and in transcription. Furthermore, DJ-1 was shown to interact with PIAS, a cofactor of the androgen receptor, but not with alpha-synuclein. Understanding the significance of these interactions will require further studies.

Finally, studies in which antibodies that recognize the DJ-1 protein were used to stain brains from patients with a variety of different neurodegenerative diseases reveal localization of this protein to neurofibrillary tangles and Pick bodies as well as reactive astrocytes, one of the major types of glial cells in the brain. Pick bodies are spherical tau inclusions similar to tangles, but most characteristic of Pick's disease, a frontotemporal dementia. Although the significance of glial pathology in neurodegeneration is not well understood, this is a new and interesting frontier of research into the mechanisms of neurodegenerative disease.

The genetics of PD

John Hardy made several points in his presentation: (i) The size of proteins that form degenerative disease lesions is relevant to neurodegeneration; (ii) diseases are dynamic processes rather than specific entities like cats and dogs; and (iii) selective vulnerability is a significant, but unexplained aspect of all neurodegenerative diseases, including those associated with parkinsonism. In other words, certain subsets of neurons in the brain appear more vulnerable to degeneration than others even when they harbor the same mutant proteins (such as alpha-synuclein or tau) or when they are exposed to the same insults (such as hypoxia caused by stroke, which is more likely to cause the death of neurons than of glial cells). Elucidation of the causes of this enigmatic selective susceptibility to degenerate is so important that doing so is likely to be recognized as a landmark breakthrough in the field. After these points were mentioned, a review and update on genetic causes of and genetic risk factors for dementing and parkinsonian neurodegenerative diseases were provided.

Recent advances in the genetics of PD

Andrew Singleton provided updates on the genetics of the Iowa "Spellman/Muenter" kindred that manifests both DLB and PD with disease onset at about 40 years of age, rather than at ~55 as seen in sporadic PD. Studies of this familial PD/DLB disorder showed that most patients displayed fibrillar deposits of alpha-synuclein, but some fibrillar tau pathology was also seen in some patients. Although the mutation associated with this familial disorder was initially linked to chromosomal region 4p, more recent studies have corrected previous interpretations of the kindred to show linkage of the disease to 4q. Because the alpha-synuclein gene is located in this region, recent efforts have focused on the reanalysis of this gene to determine whether it might be abnormal in this kindred. This reanalysis led to the discovery of a heterozygous triplication of the whole alpha-synuclein gene, without triplication of flanking genes. Thus, there is a triplication of about 1.62 to 2.04 Mb of the region containing the alpha-synuclein gene, which is associated with a ~twofold increase in alpha-synuclein protein levels in the platelets of affected versus unaffected members of the Iowa kindred. This discovery has obvious and fascinating parallels with Down syndrome.

Theme III: Cell Biology and Models

Interaction of tau and alpha-synuclein lesions in neurodegenerative diseases

Virginia M.-Y. Lee, also an author of this Perspective, reported on interactions of tau and alpha-synuclein in neurodegenerative diseases. Briefly, alpha-synuclein and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions that are characteristic of neurodegenerative diseases. However, alpha-synuclein readily assembles alone into fibrils in vitro, whereas tau fibrillization requires cofactors. Recent in vitro studies demonstrated that alpha-synuclein induces fibrillization of tau and that coincubation of tau and alpha-synuclein synergistically promotes fibrillization of both proteins. Notably, the in vivo relevance of these findings was supported by observations showing the colocalization of alpha-synuclein and tau filamentous amyloid inclusions in human patients with neurodegenerative disease, in neurons of transgenic mice expressing a mutant form of human alpha-synuclein (Ala53->Thr53, which is a pathogenic mutation that causes familial PD), and in oligodendrocytes of mice expressing WT human alpha-synuclein plus a disease-associated, mutant form of tau (Pro301->Leu301). Thus, these data suggest that interactions between alpha-synuclein and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.

In addition to these findings, there was a summary of new data obtained using antibodies that recognize Parkin (encoded by the PARK2 gene). Briefly, as discussed in greater detail below, a loss of functional Parkin (as a result of genetic mutations) has been implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism (ARJP), a movement disorder caused by loss of neurons in the substantia nigra pars compacta, which is the brainstem nucleus that undergoes severe degeneration in PD and other forms of parkinsonism. Because antibodies are critical reagents in cell biological studies of Parkin, the specificity and sensitivity of a new panel of Parkin-specific antibodies, which were generated using WT and Parkin-null mouse brain extracts, were described. Unlike previous work, these studies showed that Parkin is present only in the soluble fraction of extracts from mouse brain (regardless of the age of the mouse). In contrast, the protein is present in both the soluble and insoluble fractions of extracts from young human brain, but is found primarily in the insoluble fraction in extracts from aged human brain from healthy individuals. Furthermore, the antibodies do not stain LBs, indicating that Parkin may not be a component of LBs. Thus, these new antibodies will accelerate efforts to understand the role of Parkin in neurodegenerative diseases.

Parkin biology and biochemistry in PD

Ted Dawson focused his presentation on Parkin (see "Death Be Not Degrading"), which contains a ring finger domain and acts as an E3-type ubiquitin ligase (a type of enzyme that ubiquitinates substrate proteins and thereby targets them for degradation by the proteasome). Parkin preferentially interacts with other ring finger-containing proteins like UbcH8, a ubiquitin-conjugating enzyme. However, Parkin also interacts with and ubiquitinates the protein CDCrel-1, which is associated with synaptic vesicles. Additional Parkin substrates have also been suggested [for example, synphylin (a protein that interacts with alpha-synuclein; see "Dumpster Diving"), p38, beta-tubulin, glycosylated alpha-synuclein-P22, and PAEL-R (a G protein-coupled receptor)]. It is thought that loss-of-function mutations in Parkin result in a lack of substrate ubiquitination and degradation, thereby providing a mechanism whereby mutant Parkin could promote LB formation and thus lead to PD.

The Dawson lab is also studying parkin gene knockout (KO) mice. These mutants display a reduced startle reflex, as well as a variable age-dependent loss of both locus coeruleus and substantia nigra neurons, such that more locus coeruleus neurons are lost than substantia nigra neurons. The significance of both phenotypes is uncertain at this time. There is no evidence, however, of accumulation of any of the known Parkin substrates in these mice, although two-dimensional gels reveal increases in the concentrations of several unidentified proteins in 6-month-old, but not younger, parkin KO mice, compared to what is seen in WT mice.

Finally, LBs have recently been shown to occur in rare cases of ARJP. This phenomenon is an understudied aspect of ARJP, but these initial observations open up the possibility that a lack of functional Parkin plays a role in LB formation, although further studies are needed to confirm and extend this concept.

I fold, therefore I am: DRiPs and the protein economy of eukaryotic cells

Jon Yewdell discussed defective ribosomal products (DRiPs) and the protein economy of cells. DriPs, as reported by Schubert et al. (1), are improperly folded protein products. In the presence of proteasomal inhibitors, a 30% increase in the total protein concentration is observed in pulse-chase experiments performed using multiple cell types, including cell lines, primary lymphocyte cultures, and yeast and insect cells. But what are DRiPs? Would all of them normally be degraded quickly by the proteasome, or is something else happening? Some of these proteins are naturally short-lived and do not accumulate, whereas others may be out of equilibrium with their interacting partners and are therefore present in excess and hence are degraded. Still other rapidly degraded proteins indeed might have potential toxicity because they are misfolded, functionless, or have not been targeted to the correct location. The key accounting measures needed to place the economy of a cell in context were reviewed. Speculations were made as to the significance of this economy in neurodegenerative diseases that are associated with accumulations of misfolded proteins that form brain amyloid deposits.

Recent studies of alpha-synuclein

Peter Lansbury reviewed his hypothesis that protofibrils with pore-like morphologies are among the earliest and more important intermediates leading to amyloid fibril formation and might contribute to cytotoxicity in neurodegenerative diseases. Because the amyloid pores are unstable and might be difficult to isolate from authentic diseased brain, current efforts are directed at assembling pores in vitro from any potentially amyloid-forming peptide or protein. The aim of these experiments is to test the toxicity of the amyloid pores in cultured cells. Several subunits have been examined, including A{beta} and alpha-synuclein. There is evidence that the pores cause mitochondrial swelling by "poking" holes in organelle membranes, including mitochondrial membranes, increasing permeability that could alter mitochondrial functions. Work in the Lansbury lab is also focused on screening numerous mutant forms of alpha-synuclein to identify those that preferentially fibrillize versus those that make pores. The aim of this line of research is to determine if mutant pore-forming species can be identified that do not fibrillize. If so, the toxicity of pure pore amyloid can be assayed.

Cellular and molecular studies of normal and Leu166->Pro166 mutant DJ-1

Craig Blackstone is conducting yeast two-hybrid, immunoprecipitation, gel-exclusion, immunohistochemistry, and proteolysis inhibition studies of the WT DJ-1 protein. Self-association of DJ-1 has been seen, similar to what is observed by Peter Heutink (described above). The disease-associated Leu166->Pro166 form of DJ-1 has been shown to self-associate less well than does WT DJ-1. However, another 29-kD protein appears to associate with the mutant form, but not with WT DJ-1. The search continues for other DJ-1 binding partners. Studies using cells transfected with the DJ-1 gene show that the DJ-1 protein localizes to nuclei, mitochondria, and elsewhere in the cytoplasm. Similar localization patterns were observed for the Leu166->Pro166 mutant form of DJ-1. WT DJ-1 is more stable in transfected cells than the mutant form, although the proteasome appears to be involved in degrading both. Furthermore, the mutant protein accumulates to a greater extent in cells treated with proteasome inhibitors than does the WT protein. Thus, because the Leu166->Pro166 mutation in DJ-1 enhances degradation of DJ-1, this mutation appears to mimic, in some ways, the effects of deletion of the DJ-1 gene in the Dutch families described above. In other words, the Leu166->Pro166 mutation in DJ-1, like the genomic rearrangements, might lead to a loss of function because the mutant protein is degraded and unavailable to perform its functions. Obviously, the story on DJ-1 continues to unfold in interesting ways, but it remains to be determined what role it has in parkinsonian disorders.

Genetic and molecular analysis of a Drosophila parkin mutant

Leo Pallanck discussed work to identify a fly parkin ortholog and to generate parkin KO flies. He showed that such KO flies display male sterility, decreased life span (2/3 that of WT flies), flight and climbing defects, and structural alterations in dopaminergic neurons. Similar defects also are seen in Drosophila lines carrying point mutations in parkin. The flight defect is associated with flight muscle degeneration; the mitochondria in muscle also show pathology that precedes muscle fiber degeneration. In additional, there is evidence for apoptosis of muscle fibers. Further analysis of the sterility in parkin KO males indicated that this phenotype might reflect a germline stem cell defect (rather than a courtship or behavioral problem with mating), leading to a failure in spermatid development and individualization. Notably, here too there are defects in spermatid mitochondrial derivatives that are known as "Nebenkern," which are the energy-generating elements of spermatids. The parkin mutants do not show evidence of dopaminergic neuron loss, but neurons in these mutants showed abnormal morphologies and altered processes.

Transgenic flies that overexpress alpha-synuclein display neurodegeneration and LB formation (2). Loss of Parkin function in such flies does not increase neuronal degeneration, nor does it preclude LB formation, whereas overexpression of Parkin in flies that also overexpress alpha-synuclein does not rescue alpha-synuclein transgenic flies from neurodegeneration. This finding suggests that Parkin may not play a role in formation of LBs from alpha-synuclein.

Current work in this laboratory focuses on testing the sensitivities of parkin fly mutants to diverse chemicals and on conducting micrarray studies on mutants treated with different chemicals. These latter studies will help to map out changes in the expression of mRNAs that are linked to specific mechanistic pathways, such as those involved in the cell cycle or oxidative stress.

Chaperone-mediated autophagy and alpha-synuclein

David Sulzer reviewed the biology of chaperone-mediated autophagy (CMA). Briefly, autophogy is the lysosomal mediated protein degradation that results from large organelle engulfment (macroautophagy), such that autophagic vesicles engulf organelles and transfer them to lysosomes, ultimately leading to degradation of the proteins contained in these organelles to amino acids. This lysosomal response is usually induced by stress. On the other hand, lysosomal degradation of single proteins (microautophagy) is a constitutive process that can be the result of a CMA-type pathway. CMA initially was described by Dice and Cuervo as a degradative process that targets chaperone-bound proteins (3). This process is linked to the binding of a protein by chaperones (for example, HSP73) through a particular consensus sequence. Alpha-synuclein harbors one of these consensus sequences in the region spanning residues 95-99. In addition, levodopa (the precursor of dopamine) induces the production of more dopamine in surviving neurons of the PD brain, and dopamine metabolism is associated with the formation of neuromelanin (a mixture of degradation products that are prominent in the substantia nigra) in autophagic granules or vesicles in cultured neurons. Because there are conflicting results from studies on the role of the proteasome in the degradation of alpha-synuclein, the question has arisen as to whether or not alpha-synuclein is normally degraded by lysosomal hydrolases and whether defects in this process might play a role in PD. More work is required to resolve this question. Current data indicate that alpha-synuclein binds to and is taken up into lysosomes, and that it might be degraded by the CMA pathway. This might not be true, however, for the disease-associated Ala53->Thr53 and Ala30->Pro30 mutant forms of alpha-synuclein. Indeed, these alpha-synuclein mutants appear to bind to CMA binding sites on lysosomes, but, unlike WT alpha-synuclein, are not transported inside. This result implies that there is a transport defect for mutant alpha-synuclein that leads to the accumulation in the cytoplasm of undegraded mutant alpha-synuclein as well as other proteins. Thus, these observations prompt the speculation that mutant alpha-synuclein is impaired with respect to its lysosomal degradation, and that abnormal modifications of WT alpha-synuclein could impair its lysosomal degradation, which could be linked to neurodegeneration in PD and related synucleinopathies.

Pathophysiology of aggregated alpha-synuclein: Inhibition of the proteasome and induction of tau pathology

Ben Wolozin discussed the pathophysiology of aggregated alpha-synuclein. Briefly, transgenic mice that express a mutant form of human alpha-synuclein (Ala30->Pro30) not only exhibit alpha-synuclein aggregates, but also show increased levels of highly phosphorylated tau and tau aggregates in the same brain regions. These two types of aggregates are not always present in same neurons. However, ~40% of tau cytoplasmic staining is associated with formic acid-resistant punctate alpha-synuclein staining (which implies that tau is in a pathological, tangled state) in neuronal perikarya (cell bodies, in contrast to axons and dendrites). In comparison, less than 10% of neurons that are labeled by antibodies that recognize alpha-synuclein also show evidence of the formation of tau aggregates. Furthermore, ongoing studies suggest that the accumulation of alpha-synuclein aggregates precedes the accumulation of tau aggregates. It is interesting that alpha-synuclein aggregates somehow interact with tau, resulting in abnormal tau immunoreactivity, given the frequent convergence of tau and alpha-synuclein lesions in many patients, such as those that develop both PD and AD or DLB and AD.

Future plans are to examine the time course of the emergence of both the tau and alpha-synuclein pathology in Ala30->Pro30 alpha-synuclein transgenic mice, and to cross these mice with Parkin-overexpressing mice to see if such overexpression protects these mice from developing alpha-synuclein pathology. Other studies are intended to explore the differential role of the proteasome in alpha-synuclein degradation. Preliminary studies imply that alpha-synuclein inhibits the proteasome, such that the aggregated form has a greater inhibitory effect than the monomeric form. Gamma-synuclein, but not beta-synuclein (proteins related to alpha-synuclein), also shows proteasome-inhibitory effects. These studies will test the hypothesis that synucleins can regulate the proteasome.

The microtubule-associated protein, tau, is a CHIP substrate

Leonard Petrucelli reviewed the current understanding of the protein known as CHIP, which interacts with the carboxyl terminus of the heat shock protein Hsc70, and was originally identified as an Hsc70 co-chaperone that ubiquinates proteins and targets them for degradation. Data were presented that revealed that CHIP ubiquitinates tau and promotes its conversion from the soluble to the insoluble pool (which generally implies that the protein has precipitated out of solution and can no longer function). CHIP was also shown to stabilize the Pro301->Leu301 tau mutant isoform in the insoluble pool. Further evidence of an interaction between tau and CHIP came from the finding that antibodies that recognize CHIP stain various types of tau lesions in AD as well as in other tauopathies (such as progressive supranuclein palsy, corticobasal degeneration, and Pick's disease). There is no evidence, however, that CHIP accumulates in neurons with tau-positive pretangle structures or LBs. Finally, other ongoing studies seek to confirm and extend this work in order to dissect the role that CHIP activity might play in the normal and abnormal degradation of tau. Also of interest is how impaired CHIP function might contribute to mechanisms underlying the formation of tau pathology in neurodegenerative diseases.


This meeting provided an interesting update on recent advances in the cell biology of parkinsonian disorders, many of which are linked to abnormal protein aggregate accumulations. It is clear that our understanding of idiopathic PD and clinically similar disorders is now undergoing a paradigm shift, leading to increasing research attention on how protein misfolding is linked to neurodegeneration.

August 13, 2003
  1. U. Schubert, L. C. Anton, J. Gibbs, C. C. Norbury, J. W. Yewdell, J. R. Bennink, Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770-774 (2000). [CrossRef][Medline]
  2. M. B. Feany, W. W. Bender, A Drosophila model of Parkinson's disease. Nature 404, 394-398 (2000).[CrossRef][Medline]
  3. A. M. Cuervo, J. F. Dice, Lysosomes, a meeting point of proteins, chaperones, and proteases. J. Mol. Med. 76, 6-12 (1998).[CrossRef][Medline]
Citation: J. Q. Trojanowski, V. M.-Y. Lee, Meeting Summary--Cell Biology of Parkinson's Disease and Related Neurodegenerative Disorders. Sci. SAGE KE 2003 (32), pe23 (2003).

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