Hashimoto, Masliah and colleagues (27.14) reported that cytochrome C stimulates α-synuclein aggregration in vitro and that cytochrome C can be observed in Lewy bodies, in postmortem brain tissue. Whether cytochrome C actually plays a role in α-synuclein aggregation in vivo remains to be seen, but one could imagine a scenario in which cytochrome C release during apoptosis could promote α-synuclein aggregation. Since cytochrome C release is regulated by Bad, the link between cytochrome C and α-synuclein complements our observation that α-synuclein binds to Bad, as well as other proteins known to bind 14-3-3 including PKC, 14-3-3 itself and ERK (Ostrerova et al., 27.8; and Hanin, Petrucelli et al., 27.7).

One of the keys to understanding α-synuclein pathology will be to develop appropriate animal models. Forloni and colleagues (27.16) injected the central portion of α-synuclein, termed NAC, into substantia nigra of rats. They observed no effects associated with injecting soluble NAC, but did observe that injecting 5 ul of 500 uM pre-aggregated NAC induced neurodegeneration in the substantia nigra. Given the difficulty in showing toxicity with Aβ, the apparent toxicity of NAC is quite interesting. It is important to note that α-synuclein accumulates intracellularly in Lewy body diseases, rather than extracellularly, so the relevance of the model to disease remains to be demonstrated.

Two studies described promising results in mice over-expressing wild-type and mutant α-synuclein. Mucke and colleagues (122.10) reported on transgenic mice over-expressing wildtype α-synuclein from a PDGF promoter. Several different lines of PDGF-synuclein mice developed age-dependent neuronal inclusions resembling Lewy bodies found in Parkinson's disease and some variants of Alzheimer's disease (AD). Loss of dopaminergic terminals in the basal ganglia of these mice was associated with behavioral alterations that improved with anti-Parkinson drug treatment. Interestingly, other transgenic mice expressing high levels of wild-type α-synuclein from a Thy-1 promoter did not develop inclusions.

Yang, Hsiao and colleagues (120.13) reported on transgenic mice overexpressing α-synuclein from a PrP promoter. These mice express α-synuclein throughout the brain, and by nine months develop a progressive loss of motor function that culminates in a lack of mobility and death. Surprisingly, they do not observe any evidence of inclusion bodies in these animals, which suggests either that if α-synuclein aggregates, then they must be dispersed in the neuron rather than coalesced into inclusions. Taken together, these two sets of mice appear promising because they suggest that it will be possible to develop transgenic mice that develop Lewy body pathology, exhibit neurodegeneration and show a behavioral phenotype.

Several groups confirmed the observations by Spillantini and Trojanowski that α-synuclein accumulates in Lewy bodies. Perrin, Trojanowski, and colleagues (27.10) now report that the two homologues of α-synuclein-β- and γ-synuclein also accumulate in Lewy bodies and axonal spheroids.—Benjamin Wolozin

References:
16.3: Towards a transgenic model for Lewy body disorders. T. GOMEZ-ISLA, J. SONDEL, A. MARIASH, M. IRIZARRY, M. VAN BEUSEKOM, K. EYER, B. CHEUNG, H.B. CLARK, B.T. HYMAN AND K. HSIAO. Univ. of Minnesota, Menniapolis and Massachusetts General Hospital.

27.7: Alpha-Synuclein attenuates ERK/Elk signaling. - I. HANIN*, L. PETRUCELLI, N. OSTREROVA, M. FARRER, N. MEHTA, J. HARDY AND B. WOLOZIN Loyola Univ. Sch. of Med. and Mayo Clin. Jacksonville

27.8: Alpha-Synuclein binds to multiple proteins that regulate signal transduction pathways. - N. OSTREROVA*, L. PETRUCELLI, N. MEHTA, M. FARRER, J. HARDY AND B. WOLOZIN Loyola Univ. Med. Ctr. and Mayo Clin. Jacksonville.

27.10: Degenerating axon terminals in hippocampus of Parkinson's disease and dementia with Lewy bodies contain alpha, beta and gamma- synuclein. - J.E. GALVIN, K. URYU, V.M.-Y. LEE* AND J.Q. TROJANOWSKI MCP Hahnemann Univ. and Univ. of Pennsylvania.

27.14: Role of cytochrome c as a stimulator of amyloid-like fibril formation of alpha-synuclein/NACP. - M. HASHIMOTO, A. TAKEDA, L. HSU, T. TAKENOUCHI, A. SISK AND E. MASLIAH* Sch. of Med., UCSD.

27.16: Specific neurotoxic effect of alpha-synuclein fragment (NAC) on dopaminergic neurons. - G. FORLONI*, I. BERTANI, A.M. CALELLA AND R. INVERNIZZI Inst. of Pharmacol. Res., Mario Negri, Milan.

120.13: Amyloid-associated alpha-synuclein (NACP) pathology in aged amyloid precursor transgenic mice. - F. YANG*, G.M. COLE, K. UEDA, W. BEECH, P.-P. CHEN AND K. HSIAO VA Med. Ctr., Sepulveda, CA, UCLA, Tokyo Inst. of Psychiat. and Univ. of Minnesota.

122.10: Potential roles of alpha1-antichymotrypsin and alpha-synuclein in Alzheimer's pathogenesis assessed in bigenic mice expressing human amyloid precursor proteins. - L. MUCKE*, G.-Q. YU, C.R. ABRAHAM, L. MCCONLOGUE, E.M. ROCKENSTEIN AND E. MASLIAH UCSF, Boston Univ., Elan Pharm., South San Francisco and UCSD.

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