Reversing Neurodegeneration:A Promise Unfolds

The disappearance of aggregates in the HD mice of Yamamoto et al. suggests that mutant protein(s) can be cleared even after the cells manifest dysfunction (Figure 1Figure 1). (It also suggests that neurons have abilities of which biologists know little.) Of course, how long a neuron can withstand mutant protein before suffering irreversible damage needs to be determined. More importantly, it remains to be seen whether neurons can recover from the toxicity of full-length mutant proteins. Nevertheless, the discovery that turning off expression of even a truncated mutant protein can halt neuronal degeneration, well after behavioral and cellular dysfunction are apparent, has far-reaching implications.Figure 1A Model of Polyglutamine-Induced Neurodegeneration and Its Reversal(A) Expression of a mutant peptide with expanded polyglutamine (Q) tract leads to neuronal degeneration and eventual death. Note that both aggregated and solitary protein induce neuronal dysfunction that precedes death.(B) Turning off mutant protein expression gives the neuron enough of a reprieve to clear the mutant protein by the chaperone/ubiquitin-proteasome pathway (UPP) and subsequently recover at least some function.View Large Image | View Hi-Res Image | Download PowerPoint SlideHow might this be accomplished in humans? Turning off expression of the mutant genes or directly enhancing the clearance of the mutant proteins are two obvious answers. Before the first strategy can be successful, we must determine whether the relevant proteins are essential in adulthood. If they are, an antisense strategy might allow partial reduction or targeting of only the mutant allele. Such a strategy requires that a specific antisense approach or transcriptional manipulation be designed for each of the disease genes—and that such transcriptional manipulation would not interfere with the transcription of any other endogenous sequences.The second strategy, enhancing mutant protein clearance, has the advantage that it might apply to more than one disease, but it remains to be shown that this approach can be designed to avoid clearance of endogenous critical proteins. Factors that might enhance protein clearance include components of the UPP and the chaperone pathway. Enhancing proteasomal activity, just like interfering with transcription, might have undesirable ramifications for some key neuronal proteins. If specific proteasomal subunits play a role in substrate-specific recognition, one is again faced with the need to have a specific therapeutic approach for each of these diseases. Should future research identify a unique structural property of proteins that undergo oligomerization and accumulation in these diseases, then perhaps a strategy that enhances the activity of a protease that selectively degrades such proteins would become an option. The discovery that overexpression of HSP40 or HSP70 modulates protein aggregation and/or cell death in cell culture models of SCA1, SCA3, and ALS (6xCummings, C.J, Mancini, M.A, Antalffy, B, DeFranco, D.B, Orr, H.T, and Zoghbi, H.Y. Nat. Genet. 1998; 19: 148–154Crossref | PubMed | Scopus (668)See all References, 3xBruening, W, Roy, J, Giasson, B, Figlewicz, D.A, Mushynski, W.E, and Durham, H.D. J. Neurochem. 1999; 72: 693–699Crossref | PubMed | Scopus (193)See all References, 4xChai, Y, Koppenhafer, S.L, Bonini, N.M, and Paulson, H.L. J. Neurosci. 1999; 19: 10338–10347PubMedSee all References) and in Drosophila transgenic models of polyglutamine toxicity (Warrick et al. 1999xWarrick, J.M, Chan, H.Y, Gray-Board, G.L, Chai, Y, Paulson, H.L, and Bonini, N.M. Nat. Genet. 1999; 23: 425–428Crossref | PubMed | Scopus (570)See all ReferencesWarrick et al. 1999) is exciting and suggests a possible universal approach to this problem. Obviously, the safety of chaperone overexpression needs to be determined, and the delivery of such chaperones to the central nervous system is an open challenge.In sum, this is truly an exciting time for investigating treatment avenues for late-onset neurodegenerative diseases. The cloning of human disease genes and the study of mouse, fly, worm, and yeast models this past decade provided tremendous insight into the pathogenesis of neurodegenerative diseases. The discovery that neurons are capable of at least some recovery has provided an exciting glimpse into the future use of a new generation of mouse models. ‡E-mail: harry@mail.ahc.umn.edu (H. T. O.), hzoghbi@bcm.tmc.edu (H. Y. Z.).