Make that "blue cheese," a massive protein that is expressed in the CNS of Drosophila. In tomorrow’s Journal of Neuroscience, researchers at the Salk Institute, La Jolla, California, led by Michael McKeown of Brown University, Providence, Rhode Island, report that blue cheese mutations are involved in progressive neurodegeneration and the accumulation of protein aggregates.

Together with colleagues elsewhere, first author Kim Finley found blue cheese while working on the adjacent dissatisfaction gene on chromosome two of the fruit fly. Finley found that loss of blue cheese protein, or deletion of its first 200 amino acids, shortens the lifespan of the flies by about 40 percent. A similar fate befalls flies with insertions in blue cheese, which dramatically reduce its expression.

Blue cheese is a rather large protein, weighing in at over 380 KDa. It is expressed throughout the CNS, but not in muscle or fat tissue. The authors found it in the cytoplasm and axons of neurons, which is consistent, they write, with a role in vesicle transport or protein trafficking. Importantly, in blue cheese mutants, Finley et al. noticed that the CNS was peppered with protein aggregates that formed dark dots (and inspired the name). These turned out to contain ubiquitin and amyloid precursor-like protein and, though absent in young, day-old flies, become readily detectable by two weeks. The authors show that over a similar time frame, mutant flies exhibit signs of extensive neurodegeneration. The ommatidia of the compound eye, which have proven useful in studying fly neurodegeneration caused by mutant human proteins (see ARF related news story), begin to show signs of degeneration by day 10, and at two weeks have lost much of their distinctive morphology.

The exact function of BCHS is unknown, but several motifs in the protein offer clues. The BEACH motif, for example, is found in proteins regulating lysosomal trafficking, while the C-terminus end of the molecule contains a FYVE finger, which crops up in proteins regulating vesicle trafficking. Significantly, Finley report a high degree of conservation between Drosophila blue cheese and its human homolog ALFY, which was only recently described (Genbank accession number AF538685).-Tom Fagan.

Reference:
Finley KD, Edeen PT, Cumming RC, Mardahl-Dumesnill MD, Taylor BJ, Rodriguez MH, Hwang CE, Benedetti M, McKeown M. Blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J. Neurosci. 2003 February 15;23:1-11. Abstract

See press release.

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  1. The demonstration by Finley et al that loss of function of the blue cheese (bchs) gene in Drosophila leads to adult-stage neurodegeneration may be a very important finding, with implications for a range of neurodegenerative diseases, including Alzheimer's, Parkinson's, and ALS. Perhaps the two key findings of these studies are that the neurodegeneration is age-related, and that it is accompanied by accumulation of protein aggregates, characteristics also observed in the diseases mentioned above. Although many studies have employed invertebrate models (e.g., flies and the nematode C. elegans) to study neurodegeneration, this is the first study where loss-of-function mutations have been shown to cause age-dependent, aggregation-associated neurodegeneration.

    Although blue cheese is a novel gene, it contains protein motifs suggesting a role in vesicle and lysosomal trafficking. It is tempting to speculate that this gene functions in intracellular protein degradation, and its loss results in the eventual accumulation of aggregated proteins, which are subsequently neurotoxic. At this point, however, there is no direct evidence that the protein aggregates are causally linked to the observed neurodegeneration. It would also be nice to know if these aggregates are akin to the aggresomes implicated in the formation of Lewy bodies (McNaught et al., 2002), polyglutamine protein aggregates (Shimohata et al., 2002), and aggregates of peripheral myelin protein 22 associated with demyelinating peripheral neuropathies (Ryan et al., 2002).

    The blue cheese gene has apparent homologs in other organisms, including the ALFY genes in humans. It is possible that mutations in ALFY are involved in neurodegenerative diseases. Interestingly, a cohort of sporadic PD patients was found to have a genetic association to the 4q21 chromosomal region (the site of the ALFY gene), but polymorphism studies of NFkappaB, also located in the 421q region, failed to support a role for this candidate gene in the 4q21 region (Wintermeyer et al., 2002). The study by Finley et al. suggests that reexamining ALFY in this cohort might be informative.

    The blue cheese mutants will likely provide a useful tool for understanding neurodegeneration in general, as the powerful genetic approaches possible in Drosophila can now be applied to dissect the neurodegenerative process. Although the phenotypes of the blue cheese mutants are not particularly convenient for forward screens designed to identify suppressor or enhancer mutations, it will be nevertheless be very instructive to introduce mutations or genetic manipulations that suppress or enhance phenotypes associated with expression of human aggregating disease-associated proteins in flies (e.g., polyglutamine repeat toxicity, Fernandez-Funez et al, 2000; α-synuclein toxicity, Auluck et al., 2002). These studies may be able to directly address the generality of the role of protein aggregation in neurodegenerative processes.—Chris Link, University of Colorado, Boulder.

    References:

    Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002;295:865-868. Abstract

    McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW. Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci. 2002;16:2136-2148. Abstract

    Ryan MC, Shooter EM, Notterpek L. Aggresome formation in neuropathy models based on peripheral myelin protein 22 mutations. Neurobiol Dis. 2002;10:109-118. Abstract

    Shimohata T, Sato A, Burke JR, Strittmatter WJ, Tsuji S, Onodera O. Expanded polyglutamine stretches form an "aggresome." Neurosci Lett. 2002;323:215-218. Abstract

    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet. 1999;23:425-428. Abstract

    Wintermeyer P, Riess O, Schols L, Przuntek H, Miterski B, Epplen JT, Kruger R. Mutation analysis and association studies of nuclear factor-kappaB1 in sporadic Parkinson's disease patients. J Neural Transm. 2002;109:1181-1188. Abstract

  2. The study by McKeown and colleagues describes a novel Drosophila gene—blue cheese—that is required for the survival of neurons in aging adult flies. They show that while homozygous blue cheese mutants survive into adulthood, they exhibit a 40-45 percent reduction in adult longevity, and an age-dependent reduction in CNS volume and appearance of neurodegenerative morphologies. For example, within the compound eye, one-day-old blue cheese mutant flies exhibit normal organization of ommatidia and retinal structures, but by 10 days of age, there is retinal degeneration, condensation of individual rhabdomeres and the appearance of large vacuoles between the ommatidia. Similar atrophy is detected in the central brain, although, interestingly, there is an apparent absence of significant vacuole formation. Many neurons in the blue cheese mutants ultimately undergo apoptotic cell death, as increased numbers of TUNEL-positive cells are detected within cortical regions of the CNS. The initial viability of blue cheese mutant adults implies that, at least, zygotic functions of blue cheese are not essential for CNS development.

    The blue cheese gene encodes a large 3,492 amino acid protein that contains a BEACH domain and a cysteine-rich FYVE finger domain. Both these domains have been implicated in trafficking of lysosomes and vesicles, as well as in protein sorting and processing. Consistent with such functions, the Blue Cheese protein exhibits cytoplasmic localization and is detected in the cell bodies and projections of specific neurons within the adult optic lobes and CNS. In addition, blue cheese mutant flies exhibit an age-dependent accumulation of ubiquitin-immunoreactive aggregates throughout the CNS. These aggregates co-label with thioflavine S, suggesting that they contain abnormally folded proteins that adopt β-pleated sheet conformations. They also contain the AβPPL protein, the Drosophila homolog of the amyloid precursor protein associated with Alzheimer’s disease and detected in aggregates within degenerating human nervous system tissues. Aged blue cheese flies also exhibit high levels of insoluble ubiquitinated proteins. These insoluble aggregates may sequester toxic proteins and at least temporarily prevent them from damaging the cell. The loss of Blue Cheese function may disrupt the transport of misfolded or other ubiquitinated proteins that are normally routed to the proteasome for degradation.

    Orthologs of the Blue Cheese protein were identified in C. elegans, mice and humans, implying that Blue Cheese has a common role in neuron function or maintenance. It will be of much interest to determine if the loss of blue cheese function in other species also results in neurodegenerative phenotypes. In this regard, the authors note that the human blue cheese gene maps to a region associated with several cases of familial neurodegeneration. The identification of the blue cheese gene may, therefore, reveal a novel, conserved pathway required for neuronal survival.

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References

News Citations

  1. "Parkinson's" in a Transgenic <I>Drosophila</I>

Paper Citations

  1. . blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J Neurosci. 2003 Feb 15;23(4):1254-64. PubMed.

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  1. press release

Further Reading

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  1. . blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J Neurosci. 2003 Feb 15;23(4):1254-64. PubMed.

News

  1. In Fly Model of Tauopathy, Neurons Degenerate Without Tangles

Primary Papers

  1. . blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration. J Neurosci. 2003 Feb 15;23(4):1254-64. PubMed.