Definition: The proteasome is the complete repertoire of proteases that are produced by organisms. The ubiquitin-proteasome pathway is responsible for the degradation of many cytosolic and nuclear proteins. Proteins to be degraded by this process are first conjugated to ubiquitin and then degraded within a large cytoplasmic proteolytic organelle called the proteasome.

This pathway is thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia.

Pathology of proteasome - Pathology of proteasomal degradation

 neurodegenerative diseases (Parkinson disease, Huntington disease)

• protein misfolding and protein aggregation
• inclusion bodies and other aggregates within cells.
• aggregates often contain ubiquitin, which is the signal for proteolysis by the 26S proteasome, and chaperone proteins that are involved in the refolding of misfolded proteins.
• identification of disease-causing mutations in genes coding for several ubiquitin-proteasome pathway proteins in Parkinson disease.

Pathogenesis

 The ubiquitin-proteasome pathway is thought to be responsible for the accelerated proteolysis seen in a variety of catabolic conditions, including cancer cachexia.

 Dysfunction of ubiquitin-proteasome degradation (UPD) in neurons

Protein clearance appears to be particularly important for the viability of post-mitotic neurons. UPD dysfunction is directly implicated in several neurodegenerative disorders, the most prominent of which is Parkinson disease, the second most common neurodegenerative disorder in humans.

Mutations in the gene that encodes parkin, an E3 ubiquitin-protein ligase that is expressed highly in the brain, causes autosomal recessive juvenile parkinsonism (ARJP).

As an E3 enzyme, parkin targets several proteins for degradation, and in neuroblastoma cell lines it accumulates and is concentrated in the centrosomal region on treatment with lactacystin. Additionally, co-immunoprecipitation assays have demonstrated that parkin physically binds to gamma -tubulin both in vivo in rat brains as well as in vitro in HEK293 cells.

Furthermore, except in ARJP, Parkinson disease is usually associated with Lewy bodies - intracytoplasmic inclusions containing alpha-synuclein and ubiquitin, as well as other components that await biochemical identification.

alpha-Synuclein is a substrate of the UPD system, and the Ala53Thr and Ala30Pro mutant peptides that are found in some patients, are degraded 50% slower than those of the wild type, possibly accounting for their accelerated aggregation into fibrils of the mutant protein.

Additionally, defects in UPD probably affect the clearance of alpha-synuclein in a more generalized way, as increased intracellular protein concentration promotes alpha-synuclein aggregation through a 'molecular crowding' effect.

As such, even though alpha-synuclein is not itself a centrosomal protein, it seems that the ability of the centrosome-associated UPD system to clear misfolded proteins is central to the pathogenesis of all forms of Parkinson disease.

The emerging theme deduced from the functional properties of the Parkinson disease proteins is that defective protein degradation underlies the pathogenesis of this disease.

Therefore, given that the centrosome is linked to the UPD system both structurally and functionally, it is reasonable to propose that centrosomal dysfunction has a role in the pathogenesis of protein clearance disorders, and that the evaluation of centrosomal integrity and function in progressive phenotypes might yield new functional insights into poorly understood pathologies.

The link between centrosomal dysfunction and protein clearance disorders could be direct, for example by affecting the recruitment and/or anchoring of centrosomally located proteins such as parkin, or indirect, through the destabilization or disorganization of the pericentriolar region, where the bulk of proteasome-dependent protein degradation occurs.

As such, it might be useful to investigate not only a causative link between centrosomal dysfunction and UPD-based disorders, but also to speculate that centrosomal perturbation might be important in modulating the rate of progression and/or severity of such phenotypes.

See also

 ubiquitin-proteasome system (UPS)
 antigen processing by the proteasome
 degradation of misfolded proteins
 proteasome inhibition

References

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