Look to the lysosome—not the proteasome—for protein degradation gone awry in Parkinson's disease, suggest the authors of an article published in this week’s Science. But before you forget the proteasome, a recent article in the Journal of Biological Chemistry suggests this organelle may yet offer some insights into the secrets of protein aggregation in PD and other synucleinopathies.

The proteasome has justifiably become a target of Parkinson's researchers. There is much evidence implicating this particular arm of the cellular protein degradation machinery in the disease (see ARF related news story). Not the least of this evidence is the fact that parkin and UCH-L1 are both involved in the ubiquitin-proteasome system. However, since some studies have failed to show that α-synuclein levels are affected by proteasomal inhibition, Ana Maria Cuervo of Albert Einstein College of Medicine in Bronx, New York, and colleagues at several other institutions, suggest we turn our attention to the lysosomal autophagy arm of the protein recycling system. They note that the proteasome is typically only responsible for short-lived proteins, whereas the lysosome generally mops up cytosolic proteins with a half-life longer than 10 hours.

Working with cultured rat neurons, Cuervo and colleagues found that endogenous α-synuclein has a half-life of about 17 hours. They also found evidence that wild-type α-synuclein, both native and human, is degraded by lysosomes. The authors then asked whether α-synuclein is presented for proteolysis via macroautophagy—an indiscriminate process wherein entire cytosol regions and everything in them is vacuumed up and delivered to lysosomes—or via chaperone-mediated autophagy (CMA). A series of experiments in isolated lysosomes supported the notion that α-synuclein is chaperoned to lysosomes. For example, the researchers severely reduced lysosomal uptake of the protein by mutating a putative chaperone recognition motif on α-synuclein.

When the authors turned their attention to PD-causing α-synuclein mutations, they found that both A30P and A53T mutants had trouble getting into the lysosomes, despite the fact that they were readily recognized by CMA receptors and bound tightly to the organelle surface. Moreover, these mutants blocked lysosomal uptake and degradation of other proteins, "which may further contribute to cellular stress, perhaps causing the cell to rely on alternate degradation pathways or to aggregate damaged neurons," write the authors.

But the proteasome-PD connection may not go quietly into the night, judging by an article published online August 18 in the Journal of Biological Chemistry by Hardy J. Rideout, of Columbia University in New York City, and colleagues. In earlier work, these researchers were among the groups that demonstrated that they could induce a PD model—featuring Lewy body-like intracellular inclusions and neuronal apoptosis—by inhibiting the proteasome. The fibrillar inclusions in this model contained α-synuclein, as in Parkinson disease.

In their current study, the researchers raise the possibility that α-synuclein is not actually required for the formation of intracellular aggregates, at least in this model. Inclusions still formed—and cells died—in α-synuclein -null cells exposed to a proteasome inhibitor. However, the inclusions were not fibrillar, and the results of further experiments by Rideout and colleagues suggest that fibrillization may be α-synuclein's contribution. "The lack of effect on survival in α-synuclein knockout cultures further suggests that the fibrillar nature of the inclusions does not contribute to neuronal degeneration in this model," the authors conclude.—Hakon Heimer


  1. Mechanisms leading to the formation of α-synuclein inclusions in Parkinson's disease (PD) and related α-synucleinopathies characterized predominantly by abundant fibrillary intracellular α-synuclein inclusions in neurons and their processes as well as in glial cells (e.g., in multiple system atrophy) remain largely unknown. However, insights from studies of familial autosomal dominant forms of these disorders suggest that overproduction of α-synuclein due to α-synuclein gene triplication, or the predisposition of mutant α-synuclein to fibrillize are plausible mechanisms underlying heritable α-synucleinopathies, but less traction has been established in defining the basis for sporadic neurodegenerative α-synucleinopathies. Nonetheless, there is little evidence for overproduction of α-synuclein as a possible cause of sporadic disease. On the other hand, since sporadic α-synucleinopathies, like many other sporadic neurodegenerative brain amyloidoses (CJD, AD, PSP, CBD, etc.), involve the abnormal aggregation and fibrillization of normally soluble brain proteins that become insoluble and form brain deposits composed of similar appearing amyloid fibrils (even though the building blocks of amyloid fibrils vary in different diseases), one plausible mechanism to account for these sporadic disorders is the failure to degrade the disease brain proteins effectively when they reach a certain threshold level or concentration in a cell whether or not they are in a native or misfolded state. Indeed, impairments in proteasomal and lysosomal/autophagic degradation of disease proteins are under intense investigation, but the literature is somewhat contradictory. Thus, the recent papers by Cuervo et al. in Science and Rideout et al. in the Journal of Biological Chemistry add new insights into the role of autophagy in the degradation of α-synuclein, which may play a more direct role in α-synucleinopathies than the proteasome. Significantly, Cuervo et al. show that α-synuclein is degraded in lysosomes through a process known as the chaperone mediated autophagy (CMA) pathway, while the proteasome pathway did not appear to be involved, and known familial PD α-synuclein gene mutations blocked CMA of α-synuclein and other substrates. Further, the studies of Rideout et al. indicate that proteasomal inhibition can induce formation of ubiquitinated inclusions and apoptosis, but they showed that this can occur in neurons from α-synuclein knockout mice. These studies highlight the timeliness of intensifying research on the role of CMA, lysosomes, and the ubiquitin proteasome pathways in neurodegenerative brain amyloidoses, and it would not be surprising if impairments in more than one of these degradative pathways were involved simultaneously and to variable extents in specific forms of these disorders. Further clarity about these issues may lead to strategies for assisting the aging brain to better clear effete brain proteins so that disease proteins do not accumulate as brain amyloids and lead to brain dysfunction and degeneration.

  2. Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
    Expression levels of α-synuclein are correlated with Parkinson’s disease in several ways. The most extreme example is the finding of a triplication of the normal wild-type gene in a family with dominant PD/Lewy body disease (Singleton et al., 2003). This leads to an approximate doubling of the protein load (Miller et al., 2004), which is sufficient to produce a fulminant brain disease. If a twofold increase in α-synuclein causes such a prominent, dominantly inherited disease, then perhaps smaller changes in protein expression might be associated with the risk of sporadic PD. There are other ways in which steady-state α-synuclein levels can be affected. For example, Mike Lee’s group has recently shown that turnover of α-synuclein may be affected by neuronal differentiation, and slows with aging (Li et al., 2004). Taken together, these different observations suggest that some of the complexities of sporadic synucleinopathies may be driven, in part, by effects on the relatively simple parameter of protein stability.

    In this context, the paper by Cuervo and colleagues is important in beginning to understand some of the ways in which α-synuclein protein half-life can be affected. The observation that chaperone-mediated autophagy is important adds to the general feeling that lysosomes are a more important outlet for α-synuclein degradation than other means, such as proteasomal degradation. The paper also indicates a way to decrease protein levels of α-synuclein by increasing expression of Hsc70, or its co-chaperones (hip, hop, bag-1, Hsp40, and Hsp90). There is already some literature suggesting that chaperones can mitigate α-synuclein toxicity (e.g., Auluck et al., 2002); one wonders how much of these effects are mediated through correcting the conformation of α-synuclein and how much through inducing CMA and thus reducing the amount of α-synuclein in the cytosol.


    . Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002 Feb 1;295(5556):865-8. PubMed.

    . Stabilization of alpha-synuclein protein with aging and familial parkinson's disease-linked A53T mutation. J Neurosci. 2004 Aug 18;24(33):7400-9. PubMed.

    . Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology. 2004 May 25;62(10):1835-8. PubMed.

    . alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003 Oct 31;302(5646):841. PubMed.

Make a Comment

To make a comment you must login or register.


News Citations

  1. Parkinson's Proteins and the Proteasome—The Plot Thickens

Further Reading

Primary Papers

  1. . Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004 Aug 27;305(5688):1292-5. PubMed.
  2. . alpha-synuclein is required for the fibrillar nature of ubiquitinated inclusions induced by proteasomal inhibition in primary neurons. J Biol Chem. 2004 Nov 5;279(45):46915-20. PubMed.