Aggregates in neurodegenerative disease: crowds and power?

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease34xRiess, O., Jakes, R., and Kruger, R. Mol. Med. Today. 1998; 4: 438–444Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References34. The disease is characterized by tremor, bradykinesia, rigidity and postural instability that results primarily from a loss of dopaminergic neurons of the nigro–striatal pathway. In addition to the loss of nigral neurons, PD is also characterized by the widespread distribution of Lewy bodies, which are intracytoplasmic aggregates 5–25 μm in diameter with a dense eosinophilic core and a pale surrounding ‘halo’. As with other types of aggregates discussed here, it has been suggested that Lewy bodies might have a causative role in neurodegeneration. It is worth noting that they are not completely specific for PD and are also found in association with several other types of neurodegenerative disorders, which include some cases of Alzheimer's disease and dementia with Lewy bodies (DLB)34xRiess, O., Jakes, R., and Kruger, R. Mol. Med. Today. 1998; 4: 438–444Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References, 35xMezey, E. et al. Nat. Med. 1998; 4: 755–757Crossref | PubMed | Scopus (163)See all References. Patients with PD also exhibit Lewy neurites, which appear bloated with an unidentified proteinaceous material.It has been of great interest to establish the composition of Lewy bodies and neurites. Until recently, Lewy bodies were known to contain ubiquitin, neurofilaments and several other proteins35xMezey, E. et al. Nat. Med. 1998; 4: 755–757Crossref | PubMed | Scopus (163)See all References35. However, recent work on inherited forms of PD has added significantly to our understanding of their composition. As in the case of ALS, most cases of PD occur spontaneously. However, in a small percentage of cases, PD can be inherited in an autosomally dominant fashion34xRiess, O., Jakes, R., and Kruger, R. Mol. Med. Today. 1998; 4: 438–444Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References34. Polymeropoulos and colleagues36xPolymeropoulos, M.H. et al. Science. 1997; 276: 2045–2047Crossref | PubMed | Scopus (4389)See all References36 demonstrated that one form of familial PD was associated with a missense mutation in a protein called α-synuclein. Another mutation in the same protein has also subsequently been linked to familial PD (Ref. 34xRiess, O., Jakes, R., and Kruger, R. Mol. Med. Today. 1998; 4: 438–444Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all ReferencesRef. 34). α-Synuclein is a 140 kDa protein that is homologous to two other gene products: β- and γ-synuclein37xClayton, D.F. and George, J.M. Trends Neurosci. 1998; 21: 249–254Abstract | Full Text | Full Text PDF | PubMed | Scopus (530)See all References37. The functions of all of these proteins are unknown. α-Synuclein is found in high concentrations in the nervous system, where it is primarily localized to nerve terminals, as well as other tissues. Curiously, one of the mutations in α-synuclein that has been linked to inherited PD (a Thr to Ala substitution at residue 53) occurs normally in certain species, for example, rats and some birds, that show no evidence of developing PD (Ref. 37xClayton, D.F. and George, J.M. Trends Neurosci. 1998; 21: 249–254Abstract | Full Text | Full Text PDF | PubMed | Scopus (530)See all ReferencesRef. 37). It has been suggested that these species do not live long enough to develop the disease, although other explanations are also possible. It was subsequently shown that α-synuclein was a major component of the Lewy bodies and Lewy neurites in PD as well as in DLB (38xSpillantini, M.G. et al. Nature. 1997; 388: 839–840Crossref | PubMed | Scopus (3326)See all References, 39xSpillantini, M.G. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6469–6473Crossref | PubMed | Scopus (1358)See all References). Other members of the synuclein family were absent. Significantly, α-synuclein has also been found in aggregates in other types of neurodegenerative disease. For example, a portion of the α-synuclein molecule known as the ‘non-amyloid component’ (NAC) has been detected in the neuritic plaques of patients with Alzheimer's disease34xRiess, O., Jakes, R., and Kruger, R. Mol. Med. Today. 1998; 4: 438–444Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References, 35xMezey, E. et al. Nat. Med. 1998; 4: 755–757Crossref | PubMed | Scopus (163)See all References, 36xPolymeropoulos, M.H. et al. Science. 1997; 276: 2045–2047Crossref | PubMed | Scopus (4389)See all References. Interestingly, NAC has been shown to self aggregate in vitro37xClayton, D.F. and George, J.M. Trends Neurosci. 1998; 21: 249–254Abstract | Full Text | Full Text PDF | PubMed | Scopus (530)See all References37. In addition, α-synuclein-containing aggregates are found in glial cells in ‘multiple system atrophy’ and even in sporadic ALS (Ref. 35xMezey, E. et al. Nat. Med. 1998; 4: 755–757Crossref | PubMed | Scopus (163)See all ReferencesRef. 35). The latter observation seems of great interest in view of current speculation as to the role of glial dysfunction in ALS (Ref. 11xRothstein, J.D., Martin, L.J., and Kuncl, R.W. New Engl. J. Med. 1992; 326: 1464–1468Crossref | PubMedSee all ReferencesRef. 11). It has been suggested that the protein mutations observed in familial PD allow α-synuclein to aggregate more easily. In idiopathic PD, however, α-synuclein aggregation could be triggered by damage to the normal protein, through free-radical-mediated oxidation or some other mechanism. The widespread detection of α-synuclein in many types of aggregates in different neurodegenerative diseases has lead to the suggestion that it could be a common ‘seeding’ factor in initiating their formation.Recently, another type of gene mutation that is linked to familial PD has been discovered. Leroy et al.40xLeroy, E. et al. Nature. 1998; 395: 451–452Crossref | PubMed | Scopus (1149)See all References40 have reported that familial PD in a German family is not linked to a mutation in α-synuclein but in the enzyme ubiquitin carboxy-terminal hydrolase L1 (UCH-L1). Immunoreactivity for this protein has been previously associated with Lewy bodies, together with ubiquitin40xLeroy, E. et al. Nature. 1998; 395: 451–452Crossref | PubMed | Scopus (1149)See all References40. The enzyme, which is very abundant in the brain, normally hydrolyses the bonds between ubiquitin molecules or between ubiquitin and other molecules such as glutathione. The mutation detected by Leroy et al. leads to a decrease in the enzyme activity of UCH-L1. However, exactly how this produces PD is currently unclear, although a change in the state of ubiquitination of a key protein might be important. These results are analogous to those obtained from experiments on HD by Saudou et al. discussed above. However, it is also possible that the mutated UCH-L1 itself is prone to aggregate.The widespread detection of α-synuclein-related peptides in aggregates and the ability to manipulate aggregate formation via changes in ubiquitination are certainly important. However, the precise role of aggregates in each of the diseases discussed still remains to be defined. Answers will certainly be forthcoming from current studies on the emerging sociology of macromolecules.