Type 1A Impaired proteasome activity and accumulation of ubiquitinated substrates in a hereditary neuropathy model

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J Neurochem. 2005 Mar;92(6):1531-41.

Impaired proteasome activity and accumulation of ubiquitinated substrates in a

hereditary neuropathy model.

Fortun J, Li J, Go J, Fenstermaker A, Fletcher BS, Notterpek L.

Departments of Neuroscience and Pharmacology and Therapeutics, College of

Medicine, McKnight Brain Institute, University of Florida, Gainesville, Florida,

USA.

Accumulation of misfolded proteins and alterations in the ubiquitin-proteasome

pathway are associated with various neurodegenerative conditions of the CNS and

PNS. Aggregates containing ubiquitin and peripheral myelin protein 22 (PMP22)

have been observed in the Trembler J mouse model of Charcot-Marie-Tooth disease

type 1A demyelinating neuropathy. In these nerves, the turnover rate of the

newly synthesized PMP22 is reduced, suggesting proteasome impairment. Here we

show evidence of proteasome impairment in Trembler J neuropathy samples compared

with wild-type, as measured by reduced degradation of substrate reporters.

Proteasome impairment correlates with increased levels of polyubiquitinated

proteins, including PMP22, and the recruitment of E1, 20S and 11S to aggresomes

formed either spontaneously due to the Trembler J mutation or upon proteasome

inhibition. Furthermore, myelin basic protein, an endogenous Schwann cell

proteasome substrate, associates with PMP22 aggregates in affected nerves.

Together, our data show that in neuropathy nerves, reduced proteasome activity

is coupled with the accumulation of ubiquitinated substrates, and the

recruitment of proteasomal pathway constituents to aggregates. These results

provide novel insights into the mechanism by which altered degradation of

Schwann cell proteins may contribute to the pathogenesis of certain PMP22

neuropathies.