RGD Reference Report - Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration.

General

Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration.
Authors:	Tan, Z Sun, X Hou, FS Oh, HW Hilgenberg, LG Hol, EM Van Leeuwen, FW Smith, MA O'Dowd, DK Schreiber, SS
Citation:	Tan Z, etal., Cell Death Differ. 2007 Oct;14(10):1721-32. Epub 2007 Jun 15.
RGD ID:	10047203
Pubmed:	PMID:17571083 (View Abstract at PubMed)
PMCID:	PMC3258508 (View Article at PubMed Central)
DOI:	DOI:10.1038/sj.cdd.4402180 (Journal Full-text)
A dinucleotide deletion in human ubiquitin (Ub) B messenger RNA leads to formation of polyubiquitin (UbB)+1, which has been implicated in neuronal cell death in Alzheimer's and other neurodegenerative diseases. Previous studies demonstrate that UbB+1 protein causes proteasome dysfunction. However, the molecular mechanism of UbB+1-mediated neuronal degeneration remains unknown. We now report that UbB+1 causes neuritic beading, impairment of mitochondrial movements, mitochondrial stress and neuronal degeneration in primary neurons. Transfection of UbB+1 induced a buildup of mitochondria in neurites and dysregulation of mitochondrial motor proteins, in particular, through detachment of P74, the dynein intermediate chain, from mitochondria and decreased mitochondria-microtubule interactions. Altered distribution of mitochondria was associated with activation of both the mitochondrial stress and p53 cell death pathways. These results support the hypothesis that neuritic clogging of mitochondria by UbB+1 triggers a cascade of events characterized by local activation of mitochondrial stress followed by global cell death. Furthermore, UbB+1 small interfering RNA efficiently blocked expression of UbB+1 protein, attenuated neuritic beading and preserved cellular morphology, suggesting a potential neuroprotective strategy for certain neurodegenerative disorders.

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Cellular Component

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
cytosol	located_in	IDA		10047203	PMID:17571083	MGI
mitochondrion	located_in	IDA		10047203	PMID:17571083	MGI
nucleus	located_in	IDA		10047203	PMID:17571083	MGI

Objects Annotated

Genes (Rattus norvegicus)

Cycs (cytochrome c, somatic)

Kif1b (kinesin family member 1B)

Tp53 (tumor protein p53)

Objects referenced in this article

Gene	Cycs-ps9	cytochrome c, somatic, pseudogene 9	Rattus norvegicus

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Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration.